Note: Descriptions are shown in the official language in which they were submitted.
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COMPOSITIONS COMPRISING HUMANIZED ANTIBODIES TO TNF-LIKE
LIGAND 1A (TL1A) AND USES THEREOF
CROSS-REFERENCE TO RELATED APPLICATIONS
100011 This application claims the benefit of U.S. Provisional
Application No.
63/150,825 filed February 18, 2021; U.S. Provisional Application No.
63/180,892 filed April
28, 202 I ; U.S. Provisional Application No. 63/226,037 filed July 27, 2021;
and U.S.
Provisional Application No. 63/285,781 filed December 3, 2021, all of which
are
incorporated herein by reference in their entirety.
SEQUENCE LISTING
100021 The instant application contains a Sequence Listing which
has been submitted
electronically in ASCII format and is hereby incorporated by reference in its
entirety. Said
ASCII copy, created on February 11, 2022, is named 56884-787 601 SL.txt and is
324,684 bytes in size.
I. BACKGROUND
100031 Inflammatory bowel disease (IBD) refers to a collection of
intestinal disorders
causing inflammatory conditions in the gastrointestinal tract. Severe forms of
IBD may be
characterized by intestinal fibrosis, which is the accumulation of scar tissue
in the intestinal
wall. The primary types of IBD are ulcerative colitis (UC) and Crohn's Disease
(CD). Both
UC and CD are chronic, relapsing, remitting, inflammatory conditions of the
gastrointestinal
tract that begin most commonly during adolescence and young adulthood. UC
involves the
mucosal layer of the large intestine, and symptoms include abdominal pain and
diarrhea,
frequently with blood and mucus. CD can affect the entire thickness of the
bowel wall and all
parts of the GI tract from mouth to anus. CD symptoms include abdominal pain,
diarrhea, and
other more insidious symptoms such as weight loss, nutritional deficiencies,
and fever. The
prevalence of IBD globally is approximately 5 million and the disease affects
over 2 million
people in the US.
100041 The current standard of care for the treatment of patients
with moderate to severe
IBD are generally immunomodulatory agents that are anti-inflammatory. None of
these
therapies address fibrosis in IBD. Since the approval of the first anti-TNF
agent for the
treatment of CD in 1998, the availability of newer biological agents,
including anti-integrin,
Janus kinase (JAK) inhibitors, and anti-IL12/23 has improved the care of
moderate to severe
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UC and CD (JAK inhibitors in UC only). However, none of these subsequently
approved
therapies have demonstrated significant improvement in effect size relative to
anti-TNF.
Moreover, among those patients who do respond, up to 45% will lose response
over time.
Current therapies used in the treatment of UC and CD apply a one-size-fits-all
approach
without regard to genetic or biologic variations in the patient. Existing
approaches continue to
leave unmet patient need.
100051 The heterogeneity of disease pathogenesis and clinical
course, combined with the
variable response to treatment and its associated side effects, suggests a
targeted therapeutic
approach to treating these diseases is a desirable treatment strategy. Yet
there are very few
targeted therapies available to IBD patients, especially those patients who
may be non-
responsive to existing IBD therapies. Accordingly, there is a need for
therapeutics to treat
IBD that specifically target IBD pathogenesis.
2. SU1VIIVIARY
100061 The present disclosure provides tum or necrosis factor
ligand lA (TL1A) binding
antibodies and compositions thereof for the treatment of IBD, including severe
forms of IBD
characterized by intestinal fibrosis. In various aspects, antibodies described
herein possess
features useful for therapeutic application such as low immunogeni city,
and/or features that
facilitate antibody manufacture, such as high percentage of monomeric fraction
as measured
by size-exclusion chromatography, and/or high expression. In further aspects,
antibodies
described herein possess features useful for subcutaneous administration, such
as low
viscosity at high antibody concentration. Further aspects of the antibodies
and antibody
formulations may include high solubility, low subvisible particles, low
opalescence, no
visible particulates, and any combination thereof
100071 In one aspect, provided herein is a pharmaceutical
composition comprising an
antibody that binds to tumor necrosis factor-like protein lA (anti-TL1A
antibody) at a
concentration greater than about 150 mg/mL. In some embodiments, the
concentration is
greater than about 160, 165, 170, 175,180, 185, 190, 195, 200, 205, 210, 215,
220, or 225
mg/mL. In some embodiments, the concentration is about 160, 165, 170, 175,
180, 185, 190,
195, 200, 205, 210, 215, 220, or 225 mg/mL. In some embodiments, the
concentration is
about ISO mg/mL to about 250 mg/mL. In some embodiments, the concentration is
about 175
mg/mL to about 225 mg/mL. In one aspect, provided herein is a pharmaceutical
composition
comprising an antibody that binds to tumor necrosis factor-like protein IA
(anti-TL 1A
antibody) at a concentration greater than about 50 mg/mL. In some embodiments,
the
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concentration is greater than about 55, 60, 65, 70, 75, 80, 85, 90, 95, 100,
105, 110, 115, 120,
125, 130, 135, 140, or 145 mg/mL. In certain embodiments, the concentration is
about 55,
60, 65, 70, 75, 80, 85,90, 95, 100, 105, 110, 115, 120, 125, 130, 135,140, or
145 mg/mL.
[0008] Further provided is a pharmaceutical composition for
subcutaneous
administration, the composition comprising an antibody that binds to tumor
necrosis factor-
like protein lA (anti-TL1A antibody), wherein about 150 mg to about 500 mg of
the anti -
TLIA antibody is present in the composition.
[0009] In some embodiments, a composition herein has a total volume
of less than or
equal to about 0.5, 1, 1.5,2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6õ6.5, 7, 7.5, 8,
8.5, or 9 mL.
100101 Further provided is a pharmaceutical composition comprising
a therapeutically
effective dose of an antibody that binds to tumor necrosis factor-like protein
lA (anti-TL1A
antibody), wherein the composition has a total volume of less than or equal to
about 0.5, 1,
1.5, 2, 2.5, 3, 3.5, 4, 4.5,5, 5.5, 6õ6.5, 7, 7.5, 8, 8.5, or 9 mL.
100111 In some embodiments, a composition herein has a total volume
less than or equal
to about 9.0, 8.9, 8.8, 8.7, 8.6, 8.5, 8.4,8.3, 8.2, 8.1, 8.0, 7.9, 7.8, 7.7,
7.6,7.5, 7.4, 7.3, 7.2,
7.1, 7.0, 6.9, 6.8,6.7, 6.6, 6.5, 6.4,6.3, 6.2, 6.1, 6.0,5.9, 5.8, 5.7,
5.6,5.5, 5.4, 5.3, 5.2,5.1,
5.0, 4.9, 4.8, 4.7,4.6, 4.5, 4.4, 4.3,4.2, 4.1, 4.0, 3.9,3.8, 3.7, 3.6,
3.5,3.4, 3.3, 3.2, 3.1,3.0,
2.9, 2.8, 2.7, 2.6,2.5, 2.4, 2.3, 2.2,2.1, 2.0, 1.9, 1.8,1.7, 1.6, 1.5,
1.4,1.3, 1.2, 1.1, 1.0,0.9, or
0.8 mL. In some embodiments, a composition herein has a total volume of about
0.5 mL to
about 1.5 mL. In some embodiments, a composition herein has a total volume of
about 0.5
mL to about 2.5 mL. In some embodiments, a composition herein has a total
volume of about
0.5 mL to about 3.5 mL. In some embodiments, a composition herein has a total
volume of
about 0.5 mL to about 4.5 mL. In some embodiments, a composition herein has a
total
volume of about 1 mL to about 1.5 mL. In some embodiments, a composition
herein has a
total volume of about 1 mL to about 2.5 mL. In some embodiments, a composition
herein has
a total volume of about 1 mL to about 3.5 mL. In some embodiments, a
composition herein
has a total volume of about 1 mL to about 4.5 mL. In some embodiments, a
composition
herein has a viscosity of less than about 20 cP or 10 cP.
[0012] Further provided is a pharmaceutical composition comprising
a therapeutically
effective dose of an antibody that binds to tumor necrosis factor-like protein
lA (anti-TL1A
antibody) in a pharmaceutical composition having a viscosity of less than
about 20 cP or 10
cP.
[0013] In some embodiments, a composition herein has a viscosity of
less than about 9, 8,
7, 6, or 5 cP. In some embodiments, a composition herein has a viscosity of
about 1 cP to
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about 7 cP, about 1 cP to about 2 cP, or about 10 cP to about 20 cP.
[0014] Further provided is a pharmaceutical composition comprising
a therapeutically
effective dose of an antibody that binds to tumor necrosis factor-like protein
lA (anti-TL1A
antibody), wherein the composition has a percentage aggregation of anti-TL1A
antibody as
measured by size exclusion chromatography of less than about 5% of the total
anti-TL1A
antibody in the composition.
[0015] In some embodiments, a composition herein has a percentage
aggregation of anti-
TL1A antibody as measured by size exclusion chromatography of less than about
5% of the
total anti-TL1A antibody in the composition. In some embodiments, the
aggregation is less
than about 4.5, 4, 3.5,3, 2.5, 2, 1.5, 1, or 0.5%.
[0016] In some embodiments, a composition herein comprises a
surfactant. In some
embodiments, a composition herein comprises a salt. In some embodiments, a
composition
herein comprises a stabilizer. In some embodiments, a composition herein
comprises a
buffering agent. In some embodiments, a composition herein has a pH of about
4.5 to about
8Ø
[0017] Further provided is a pharmaceutical composition comprising
an antibody that
binds to tumor necrosis factor-like protein 1A (anti-TL1A antibody) and a
surfactant.
[0018] Further provided is a pharmaceutical composition comprising
an antibody that
binds to tumor necrosis factor-like protein lA (anti-TL1A antibody) and a
salt.
[0019] Further provided is a pharmaceutical composition comprising
an antibody that
binds to tumor necrosis factor-like protein lA (anti-TL1A antibody) and a
stabilizer.
[0020] Further provided is a pharmaceutical composition comprising
an antibody that
binds to tumor necrosis factor-like protein lA (anti-TLIA antibody) and a
buffering agent.
[0021] Further provided is a pharmaceutical composition comprising
an antibody that
binds to tumor necrosis factor-like protein IA (anti-TLIA antibody), wherein
the
composition has a pH of about 4.5 to about 8Ø
[0022] In some embodiments, the surfactant comprises a nonionic
surfactant. In some
embodiments, the nonionic surfactant comprises polysorbate-20. In some
embodiments, the
surfactant is present at a concentration of about 0.005% to about 0.05% of the
composition.
In some embodiments, the surfactant is present at a concentration of about
0.01% to about
0.02% of the composition. In some embodiments, the surfactant is present at a
concentration
of about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.009%, about
0.01%,
about 0.011%, about 0.012%, about 0.013%, about 0.014%, about 0.015%, about
0.016%,
about 0.017%, about 0.018%, about 0.019%, about 0.02%, about 0.021%, about
0.022%,
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about 0.023%, about 0.024%, about 0.025%, about 0.026%, about 0.027%, about
0.028%,
about 0.029%, or about 0.03% (v/v) of the composition.
100231 In some embodiments, the salt comprises sodium chloride,
glycine, lysine-
hydrochloride, arginine-hydrochloride, arginine glutamate, potassium chloride,
magnesium
chloride, or calcium chloride, or a combination thereof. In some embodiments,
the salt
comprises sodium chloride. In some embodiments, the salt comprises lysine-HC1.
In some
embodiments, the salt is present at a concentration of about 10 mM to about
100 mM in the
composition. In some embodiments, the salt is present at a concentration of
about 25 mM in
the composition. In some embodiments, the salt is present at a concentration
of about 40 mM
in the composition.
100241 In some embodiments, the stabilizer comprises a sugar,
polyol, amino acid, or
polymer, cyclodextrin (e.g., HP-b-CD), or a combination thereof. In some
embodiments, the
stabilizer comprises the sugar. In some embodiments, the sugar comprises
sucrose, glucose,
trehalose, maltose, or lactose, or a combination thereof. In some embodiments,
the sugar
comprises sucrose. In some embodiments, the amino acid comprises glycine. In
some
embodiments, the stabilizer is present at a concentration of about 50 mM to
about 300 mM in
the composition. In some embodiments, the stabilizer is present at a
concentration of about
200 mM to about 280 mM. In some embodiments, the stabilizer is present at a
concentration
of about 220 to about 240 mM. In certain embodiments, the stabilizer is
present at a
concentration of about 150 mM, about 160 mM, about 170 mM, about 180 mM, about
190
mM, about 200 mM, about 210 mM, about 220 mM, about 230 mM, about 240 mM, or
about
250 mM.
100251 In some embodiments, the stabilizer comprises sucrose and
glycine. In certain
embodiments, the sucrose is present at a concentration of about 150 mM, about
160 mM,
about 170 mM, about 180 mM, about 190 mM, about 200mM, about 210 mM, about 220
mM, about 230 mM, about 240 mM, or about 250 mM. In some embodiments, the
glycine is
present at a concentration of about 10 mM, about 15 mM, about 20 mM, about 25
mM, about
30 mM, about 35 mM, about 40 mM, about 45 mM, about 50 mM, about 55 mM, about
60
mM, about 65 mM, about 70 mM, about 75 mM, about 80 mM, about 85 mM, about 90
mM,
about 95 mM, about 100 mM, about 105 mM, about 1 1 0 mM, about 115 mM, or
about 120
mM.
100261 In some embodiments, the buffering agent comprises acetate,
phosphate, citrate,
glutamate, succinate, gluconate, histidine, glycylglycine, citric acid, Tris
(tris
(hydroxymethyl) aminomethane), or diethanolamine, or a combination thereof. In
some
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embodiments, the buffering agent comprises acetate. In some embodiments, the
buffering
agent comprises phosphate. In some embodiments, the buffering agent is present
at a
concentration of about 10 mM to about 50 mM in the composition. In some
embodiments, the
composition comprises about 20 mM buffer.
100271 In some embodiments, the composition has a pH of about 4.5
to about 7.5. In
some embodiments, the composition has a pH of about 6 to about 7. In some
embodiments,
the composition has a pH of about 6.5. In some embodiments, the composition
has a pH of
about 5 to about 5.5. In some embodiments, the composition has a pH of about
5.3.
100281 Further provided is a method of treating an inflammatory
disease in a subject, the
method comprising administering to the subject an antibody that binds to tumor
necrosis
factor-like protein lA (anti-TL1A antibody), wherein the anti-TL1A antibody is
administered
to the subject at a first dose up to about 1000 mg. In some embodiments, the
first dose is
about 150 mg to about 1000 mg. In some embodiments, the first dose is about
500 mg to
about 1000 mg. In some embodiments, the first dose is about 500 mg or about
800 mg. In
some embodiments, the first dose is administered to the subject at a first
time point, and a
second dose is administered to the subject at a second time point. In some
embodiments, the
second time pointis about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13,14, 15,16,
17,18, 19,20, 21,
22, 23, 24, 25, 26, 27,28, 29,30, or 31 days after the first time point. In
some embodiments,
the second time point is about 1, 2, 3, or 4 weeks after the first time point.
In some
embodiments, the second dose comprises up to about 1000 mg anti-TL1A. In some
embodiments, the second dose comprises about 150 mg to about 1000 mg. In some
embodiments, the second dose comprises about 150 mg to about 600 mg. In some
embodiments, a third dose of anti-TL1A is administered to the subject at a
third time point. In
some embodiments, the third time point is about 1, 2, 3, 4, 5, 6, 7, 8, 9,
10,11, 12,13, 14,15,
16, 17, 18, 19, 20, 21,22, 23,24, 25,26, 27,28, 29,30, or 31 days after the
second time
point. In some embodiments, the third time point is about 1, 2, 3, or 4 weeks
after the second
time point. In some embodiments, the third dose comprises up to about 1000 mg
anti-TL1A.
In some embodiments, the third dose comprises about 150 mg to about 1000 mg.
In some
embodiments, the third dose comprises about 150 mg to about 600 mg. In some
embodiments, a fourth dose of anti-TL1A is administered to the subject at a
fourth time point
In some embodiments, the fourth time point is about 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, 12, 13, 14,
15, 16, 17, 18, 19, 20,21, 22,23, 24, 25, 26, 27, 28, 29, 30, or 31 days after
the third time
point. In some embodiments, the fourth time point is about 1, 2, 3, or 4 weeks
after the third
time point. In some embodiments, the fourth dose comprises up to about 1000 mg
anti-TL1A.
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In some embodiments, the fourth dose comprises about 150 mg to about 1000 mg.
In some
embodiments, the fourth dose comprises about 150 mg to about 600 mg. In some
embodiments, a fifth dose of anti-TLIA is administered to the subject at a
fifth time point. In
some embodiments, the fifth time point is about 1, 2, 3, 4, 5,6, 7, 8,9, 10,
11, 12, 13, 14, 15,
16, 17, 18, 19, 20, 21,22, 23,24, 25,26, 27,28, 29,30, or 31 days after the
fourth time point
In some embodiments, the fifth time point is about 1, 2, 3, or 4 weeks after
the fourth time
point. In some embodiments, the fifth dose comprises up to about 1000 mg anti-
TL I A. In
some embodiments, the fifth dose comprises about 150 mg to about 1000 mg. In
some
embodiments, the fifth dose comprises about 150 mg to about 600 mg. In some
embodiments,
a sixth dose of anti-TLIA is administered to the subject at a sixth time
point. In some
embodiments, the sixth time point is about I, 2, 3,4, 5, 6, 7, 8, 9, 10, 11,
12, 13, 14, 15, 16,
17, 18, 19, 20, 21, 22, 23, 24,25, 26, 27, 28, 29, 30, or 31 days after the
fifth time point. In
some embodiments, the sixth time point is about 1, 2, 3, or 4 weeks after the
fifth time point.
In some embodiments, the sixth dose comprises up to about 1000 mg anti-TLIA.
In some
embodiments, the sixth dose comprises about 150 mg to about 1000 mg. In some
embodiments, the sixth dose comprises about 150 mg to about 600 mg.
100291 In some embodiments, an additional dose of the anti-TLI A
antibody is
administered to the subject at one or more additional time points. In some
embodiments, the
one or more additional time points comprises about 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, 12, 13, 14,
15, 16, 17, 18, 19, 20,21, 22,23, or 24 additional time points. In some
embodiments, the
composition is administered to the subject at about 12 additional time points.
In some
embodiments, each additional time point is independently about 1, 2, 3, 4, 5,
6, 7, 8, 9, 10, 11,
12, 13, 14, 15, 16, 17,18, 19,20, 21,22, 23,24, 25,26, 27, 28, 29,30, or 31
days after a
previous time point. In some embodiments, each additional time point is
independently about
1, 2, 3, or 4 weeks after a previous time point. In some embodiments, at least
one of the
additional time points is about 2 weeks after the previous time point. In some
embodiments,
the additional dose comprises up to about 1000 mg anti-TLIA. In some
embodiments, the
additional dose comprises from about 150 mg to about 1000 mg anti-TL I A. In
some
embodiments, the additional dose is about 175 mg to about 300 mg anti-TLIA. In
some
embodiments, the composition comprises the composition of any one of the
embodiments
herein.
100301 In one aspect, provided herein is an antibody or antigen
binding fragment thereof
that binds to tumor necrosis factor-like protein 1A ("TL1 A," and such
antibody or antigen
binding fragment thereof, "anti-TL1A antibody or antigen binding fragment"),
wherein the
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antibody or antigen binding fragnent binds to both monomeric TL1A and trimeric
TL1A.
[0031] In some embodiments, the antibody or antigen binding
fragment blocks
interaction of TL1A to Death Receptor 3 ("DR3"). In some embodiments, the
binding
affinity of the antibody or antigen binding fragment to monomeric TL1A as
measured by
dissociation equilibrium constant (KD-monomer) is comparable to binding
affinity of the
antibody or antigen binding fragment to trimeric TL as measured by
dissociation
equilibrium constant (KD-ttimet)= In some embodiments, the KD-monomet is
within 1.5, 2, 3, 4, 5,
6, 7, 8, 9, or 10 fold of the KD-trimer. In some embodiments, the KD-monomer
is no more than
0.06 nM. In some embodiments, the KD-tnmer iS no more than 0.06 nM.
[0032] In one aspect, provided herein is a method of neutralizing
monomeric TL1A and
trimeric TL1A in a subject comprising (a) administering an effective dose of
anti-TL1A
antibody or antigen binding fragment to the subject, wherein the antibody or
antigen binding
fragment binds to both monomeric TL1A and trimeric TL1A, and wherein the
antibody or
antigen binding fragment blocks interaction of TL to DR3. In some embodiments,
the
concentration of TL in a diseased tissue in the subject is reduced
below the concentration
of TL1A in a corresponding tissue in a control subject without IBD. In some
embodiments,
the subject has IBD.
[0033] In one aspect, provide herein is a method of reducing the
concentration of TL1A
in a diseased tissue in a subject with inflammatory bowel disease ("IBD")
comprising (a)
administering an effective dose of anti-TL1A antibody or antigen binding
fragment to the
subject, thereby reducing the concentration of TL1A in the diseased tissue in
the subject
below the concentration of TL1A in a corresponding tissue in a control subject
without MD.
[0034] In one aspect, provide herein is a method of treating IBD in
a subject in need
thereof comprising (a) administering an anti -TL1A antibody or antigen binding
fragment to
the subject, wherein the anti-TL1A antibody or antigen binding fragment is
administered at
an effective dose such that the concentration of TL1A in a diseased tissue in
the subject after
step (a) is below the concentration of TL1A in a corresponding tissue in a
control subject
without IBD.
[0035] In one aspect, provide herein is a method of treating IBD in
a subject in need
thereof comprising (a) administering an anti-TL1A antibody or antigen binding
fragment to
the subject at an effective dose, and (b) reducing the concentration of TL1A
in a diseased
tissue in the subject below the concentration of TL1A in a corresponding
tissue in a control
subject without IBD.
[0036] In some embodiments, the effective dose comprises an
induction regimen.
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100371 In some embodiments, the method further comprises (c)
maintaining TL in the
diseased tissue in the subject at a concentration below the concentration of
TL in the
corresponding tissue in the control subject.
100381 In some embodiments, the TL1A in the diseased tissue in the
subject is maintained
with a maintenance regimen of the anti-TL1A antibody or antigen binding
fragment. In some
embodiments, the induction regimen and the maintenance regimen are identical.
In some
embodiments, the induction regimen and the maintenance regimen are different.
In some
embodiments, the maintenance regimen is administered after the induction
regimen. In some
embodiments, the diseased tissue in the subject produces up to 50, 60, 70,80,
90, 100, or
more fold of TL1A compared to the corresponding tissue in the control subject
during the
induction regimen. In some embodiments, the diseased tissue in the subject
produces up to
50, 60, 70, 80, 90, 100, or more fold of TL1A compared to the corresponding
tissue in the
control subject within 1, 2, 3, 4, 5, or 6 weeks of start of the induction
regimen. In some
embodiments, the diseased tissue in the subject produces up to 50, 60, 70,80,
90, 100, or
more fold of TL1A compared to the corresponding tissue in the control subject.
100391 In some embodiments, the induction regimen comprises a one-
time administration
of the anti-TL1A antibody or antigen binding fragment. In some embodiments,
the anti-
TL1A antibody or antigen binding fragment is administered at 200 mg/dose, 250
mg/dose,
300 mg/dose, 350 mg/dose, 400 mg/dose, 450 mg/dose, 500 mg/dose, 550 mg/dose,
600
mg/dose, 650 mg/dose, 700 mg/dose, 750 mg/dose, 800 mg/dose, 850 mg/dose, 900
mg/dose,
950 mg/dose, 1000 mg/dose, 1100 mg/dose, 1200 mg/dose, 1250 mg/dose, 1300
mg/dose,
1400 mg/dose, 1500 mg/dose, 1600 mg/dose, 1700 mg/dose, 1750 mg/dose, 1800
mg/dose,
1900 mg/dose, or 2000 mg/dose.
100401 In some embodiments, the induction regimen comprises
multiple administrations
of the anti-TL1A antibody or antigen binding fragment. In some embodiments,
the induction
regimen comprises administrations of (i) 1000 mg/dose on week 0, 1000 mg/dose
on week 2,
1000 mg/dose on week 6, and 1000 mg/dose on week 10; (ii) 500 mg/dose on week
0, 500
mg/dose on week 2, 500 mg/dose on week 6, and 500 mg/dose on week 10; (iii)
1000
mg/dose on week 0, 1000 mg/dose on week 2, 1000 mg/dose on week 6, and 500
mg/dose on
week 10; (iv) 1000 mg/dose on week 0, 1000 mg/dose on week 2, 500 mg/dose on
week 6,
and 500 mg/dose on week 10; or (v) 1000 mg/dose on week 0, 500 mg/dose on week
2, 500
mg/dose on week 6, and 500 mg/dose on week 10.
100411 In some embodiments, the induction regimen comprises
administration of 2000,
1950, 1900, 1850, 1800, 1750, 1700, 1650, 1600, 1550, 1500, 1450, 1400,1350,
1300, 1250,
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1200, 1150, 1100, 1050, 1000, 950, 900, 850, 800, 750, 700, 650, 600, 550,
500, 450, 400,
350, 300, 250, or 200 mg/dose. In some embodiments, the induction regimen
comprises
administration once every 2, 4, 6, or 8 weeks. In some embodiments, the
induction regimen
comprises administration once every 2 or 4 weeks for the first 2
administrations and then
once every 2, 4, 6, or 8 weeks for the remaining induction regimen.
100421 In some embodiments, the diseased tissue in the subject
produces up to 10, 15, 20,
25, 30, 35, 40, 45, 50, or more fold of TL1A compared to the corresponding
tissue in the
control subject. In some embodiments, the diseased tissue in the subject
produces up to 10,
15, 20, 25, 30, 35, 40,45, 50, or more fold of TL1 A compared to the
corresponding tissue in
the control subject during the maintenance regimen. In some embodiments, the
diseased
tissue in the subject produces up to 10, 15, 20,25, 30,35, 40, 45, 50, or more
fold of TL1A
compared to the corresponding tissue in the control subject within 1, 2, 3, 4,
5, 6, 7, 8,9, 10,
11, 12, 14, 16, 18, 20, 22, 24,28, 32, 36, 40, 44, 48, or 52 weeks, or longer
of start of the
maintenance regimen.
100431 In some embodiments, the maintenance regimen comprises
multiple
administrations of the anti-TL1A antibody or antigen binding fragment. In some
embodiments, the maintenance regimen comprises administrations of the anti-
TL1A antibody
or antigen binding fragment at (i) 500 mg/dose every 2 weeks, (ii) 400 mg/dose
every 2
weeks, (iii) 300 mg/dose every 2 weeks, (iv) 250 mg/dose every 2 weeks, (v)
200 mg/dose
every 2 weeks, (vi) 150 mg/dose every 2 weeks, (vii) 100 mg/dose every 2
weeks, (viii) 50
mg/dose every 2 weeks, (ix) 500 mg/dose every 4 weeks, (x) 400 mg/dose every 4
weeks,
(xi) 300 mg/dose every 4 weeks, (xii) 250 mg/dose every 4 weeks, (xiii) 200
mg/dose every 4
weeks, (xiv) 150 mg/dose every 4 weeks, (xv) 100 mg/dose every 4 weeks, (xvi)
50 mg/dose
every 4 weeks, (xvii) 500 mg/dose every 6 weeks, (xviii) 400 mg/dose every 6
weeks, (xix)
300 mg/dose every 6 weeks, (xx) 250 mg/dose every 6 weeks, (xxi) 200 mg/dose
every 6
weeks, (xxii) 150 mg/dose every 6 weeks, (xxiii) 100 mg/dose every 6 weeks,
(xxiv) 50
mg/dose every 6 weeks, (xxv) 500 mg/dose every 8 weeks, (xxvi) 400 mg/dose
every 8
weeks, (xxvii) 300 mg/dose every 8 weeks, (xxviii) 250 mg/dose every 8 weeks,
(xxix) 200
mg/dose every 8 weeks, (xxx) 150 mg/dose every 8 weeks, (xxxi) 100 mg/dose
every 8
weeks, or (xxxii) 50 mg/dose every 8 weeks.
100441 In some embodiments, the maintenance regimen comprises
administration of the
anti-TL1A antibody or antigen binding fragment at 1000, 950, 900, 850, 800,
750, 700, 650,
600, 550, 500, 450, 400,350,300, 250,200, 150, 100, or 50 mg/dose. In some
embodiments,
the maintenance regimen comprises administration of the anti-TL1A antibody or
antigen
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binding fragment once every 2, 4, 6, 8, 10, or 12 weeks. In some embodiments,
the
maintenance regimen comprises administrations of the anti-TL1A antibody or
antigen
binding fragment at 250 mg/dose every 4 weeks. In some embodiments, the
maintenance
regimen comprises administrations of the anti-TL1A antibody or antigen binding
fragment at
100 mg/dose every 4 weeks. In some embodiments, the maintenance regimen
continues for
4, 6, 8, 10, 12, 14, 16, 18, 20,22, 24,26, 28,30, 32,34, 36,40, 44, 48, or 52
weeks.
100451 In some embodiments, the antibody or antigen binding
fragment binds to both
monomeric TL1A and trimeric TL1A and wherein the antibody or antigen binding
fragment
blocks binding of TL1A to DR3. In some embodiments, at least 60%, 65%, 70%,
75%, 80%,
85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%
of
the monomeric TL1A in the blood of the subject is occupied by the anti-TL1A
antibody or
antigen binding fragment. In some embodiments, at least 60%, 65%, 70%, 75%,
80%, 85%,
86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the
trimeric TL1A in the blood of the subject is occupied by the anti-TL1A
antibody or antigen
binding fragment.
100461 In some embodiments, the binding affinity of the antibody or
antigen binding
fragment to monomeric TL as measured by dissociation equilibrium constant (KD-
monomet)
is comparable to binding affinity of the antibody or antigen binding fragment
to trimeric
TL1A as measured by dissociation equilibrium constant (1(Dtrimõ). In some
embodiments,
the KD-monomer is within 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or 10 fold of the KD-
trimer. In some
embodiments, the KD-monomer is no more than 0.06 nM. In some embodiments, the
KD-trimer 1S
no more than 0.06 nM.
100471 In some embodiments, the IBD is Crohn's disease or
ulcerative colitis.
100481 In some embodiments, the diseased tissue comprises any one
or more selected
from the group consisting of colon, small intestine, rectum, cecum, ileum,
spleen, a fibrotic
tissue from IBD, and other tissues with IBD pathology, and other tissues of
IBD
pathogenesis.
100491 In some embodiments, the effective dose or the induction
regimen is determined
by a dose determination method, wherein the dose determination method
comprises: (i)
receiving a parameter of TL over-production in the diseased tissue comparing
to TL
production in a normal reference tissue; (ii) integrating the parameters
received in (a) to an
integrated whole-body physiologically based pharmacokinetic (PBPK) model or a
population
pharmacokinetic model (popPK); and (iii) determining the effective dose or the
induction
regimen such that the concentration of TL1A in diseased tissue in the subject
after step (a) is
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below the concentration of TL1A in a corresponding tissue in a control subject
without IBD.
In some embodiments, the parameter of TL1A over-production is 10, 15, 20,25,
30,35, 40,
45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160,
170, 180, 190,
200, or more fold over-production comparing to TL1A production in the normal
reference
tissue.
100501 In some embodiments, the maintenance regimen is determined
by a dose
determination method, wherein the dose determination method comprises: (i)
receiving a
parameter of TL over-production in the diseased tissue comparing to TL
production in
a normal reference tissue; (ii) integrating the parameter received in (i) to
an integrated whole-
body physiologically based pharmacokinetic (PBPK) model or a population
pharmacokinetic
model (popPK); and (iii) determining the maintenance regimen such that the
concentration of
TL1A in diseased tissue in the subject after step (c) is below the
concentration of TL1A in a
corresponding tissue in a control subject without IBD. In some embodiments,
the parameter
of TL1A over-production is 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70,
75, 80, 85, 90,
95, 100, or more fold over-production comparing to TL1A production in the
normal reference
tissue.
100511 In some embodiments, the step (i) in the dose determination
method further
comprises receiving association rate of the antibody to TL1A (kon..Ab),
dissociation rate of
the antibody from TL1A (kofflmAb), synthesis rate of TL1A in normal tissue
(k1101),
synthesis rate of TL in diseased tissue (ksyn-cusease), and/or
degradation rate of TL (( deg-
total-TL1A). In some embodiments, the association rate of the antibody to TL
(kon-mAb)
comprises the association rate of the antibody to monomeric ILIA (k on-
monomer) and
association rate of the antibody to trimeric TL1A 0õ-tnmet), wherein the
dissociation rate of
the antibody from TL1A (koffiniAb) comprises the dissociation rate of the
antibody from
monomeric TL1A (koff_mo.,) and dissociation rate of the antibody from trimeric
TL1A (kofr_
trimet), and/or wherein the degradation rate of TL
(k deg-total-TL1A) comprises degradation rate
of monomeric TL1A (kdeg-TLIA-monomer) and degradation rate of trimeric
TL1A(kdeg-TL1A-trimet)=
100521 In some embodiments, the step (i) in the dose determination
method further
comprises receiving association rate of the antibody to FcRn receptor (k on-
mAb-FeRn),
dissociation rate of the antibody from FcRn (k off- mAb cKn), association rate
of the antibody-
TL1A complex to FcRn receptor (kon-(rnAb-TuA)-FcR.), and/or dissociation rate
of the antibody -
TL1A complex from FcRn off-(m Ab-TL1 A)-FeRn). In some embodiments, the
association rate of
the antibody- TL1A complex to FeRn receptor (k on-(rnAb-TLIA)-FcRn) Comprises
association rate
of the antibody -monomeric-TL1A complex to FcRn receptor (kon-(mAb-monoTLIA)-
FcRn) and
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association rate of the antibody-trimeric-TL1A complex to FcRn receptor
(koõ.(mAb -triTL 1A)-
FeRn), and/or wherein the dissociation rate of the antibody- TLIA complex from
FcRn (kar_
(niAb-miA)-FcRn) comprises dissociation rate of the antibody-monomeric-TL1A
complex from
FcRn (ketr-(fflAb-monoTL1A)-FcRn) and dissociation rate of the antibody -
trimeric-TLIA complex
from FcRn (k0ff-(mAb-triTL1A)-FcRn).
100531 In some embodiments, the step (i) in the dose determination
method further
comprises receiving clearance rate of FcRn receptor bound by the antibody
(kdeg-mAb-rcRn). In
some embodiments, the clearance rate of FcRn receptor bound by the antibody
(kdeg-niAb-FeRn)
comprises clearance rate of the antibody to FcRn bound by the antibody-
monomeric-TL1A
complex (kdeg-(mAb-monomim-rcRii) and clearance rate of FcRn receptor bound by
the antibody -
trimeric-TL1A complex (kcteg-(mAb-itimim-FeRn). In some embodiments, in the
dose
determination method: (1) kon_monomõand kon_trimõ are identical or different;
(2) koff_monomõand
koff_iiimer are identical or different; (3) kdeg_monomer and kdegt,imer are
identical or different; (4)
kon-(mAb -mono TL 1A)-FcRn and k0n.(mAb-ttiTL1A)-FcRn are identical or
different; (5) kon_mAb-FcRn and kon-
(mAb -monoTL1A)-FcRn are identical or different; (6) kon-mAb-FcRn and kon-(mAb-
triTL1A)-FcRn are identical
or different; (7) k off-(mAb -mono 1A)-FcRn and koff-(mAb-ttiTL1A)-FeRn are
identical or different; (8) k off-
mAb -FcRn and koff-(mAb-monnTL1A)-FcRn are identical or different; (9) koff-
mAb-FcRn and koff-(mAb-
ttiTL 1 A)-FcRn are identical or different; (10) kdeg-(n1 Ab-mcncT1-1 A)-FcRn
and kdeg-(m Ab -tri TL 1 A)-FcRn are
identical or different; (11) kdeg-mAb-FcRn and kdeg-(nAb-triTL1A)-FcRn are
identical or different; (12)
kdeg-mAb-FcRn and kdeg-(mAb-monoTL A)-FcRn are identical or different; (13)
any combination of (I)
to (12). In some embodiments, in the dose determination method: ksvn-disease
is up to 10, 15,
20, 25, 30, 35, 40, 45,50, 55, 60, 65,70, 75,80, 85,90, 95,100,110,120,
130,140,150,
160, 170, 180, 190, 200, or more fold of ksyn_normai. In some embodiments, the
step (i) in the
dose determination method further comprises receiving rate of TL1A trim
erization (k on_Th A_
monomcr-to -trimet) and/or rate of TLIA monomerization (k offr_u_ JA-trimcr-to
-monomer) =
100541 In one aspect, provided herein is a method of determining an
effective dose
regimen for administering an anti-TLIA antibody to a subject with IBD, wherein
the method
comprises: (a) receiving a parameter of TL1A over-production in the diseased
tissue
comparing to TLIA production in a normal reference tissue; (b) integrating the
parameter
received in (a) to an integrated whole-body physiologically based
pharmacokinetic (PBPK)
model; and (c) determining the effective dose regimen of the anti-TLI A
antibody with the
PBPK model from (b) such that after administration of the effective dose
regimen the
concentration of TLIA in a diseased tissue in the subject is below the
concentration of TLIA
in a corresponding tissue in a control subject without EBD.
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100551 In one aspect, provided herein is a method of determining an
effective dose
regimen for administering an anti-TL1A antibody to a subject with IBD, wherein
the method
comprises: (a) receiving a parameter of TL1A over-production in the diseased
tissue
comparing to TL1A production in a normal reference tissue; (b) integrating the
parameter
received in (a) to a population pharmacokinetic (popPK) model; and (c)
determining the
effective dose regimen of the anti-TL1A antibody with the popPK model from (b)
such that
after administration of the effective dose regimen the concentration of TL 1 A
in a diseased
tissue in the subject is below the concentration of TL1A in a corresponding
tissue in a control
subject without IBD.
100561 In some embodiments of the dose determination methods, the
parameter of TL1A
over-production is 10, 15,20, 25,30, 35, 40, 45,50, 55, 60, 65, 70, 75, 80,
85, 90, 95,100,
110, 120, 130, 140, 150, 160, 170, 180, 190, 200 or more fold over-production
comparing to
TL1A production in the normal reference tissue. In some embodiments of the
dose
determination methods, the step (a) further comprises receiving association
rate of the
off-
antibody to TL1A (koõm
-Ab), dissociation rate of the antibody from TL1A (kmAb), synthesis
rate of TL1A in normal tissue (ksyn-nonnal), synthesis rate of 'TL1A in
diseased tissue
disease), and/or degradation rate of TL (k deg-total-TL
100571 In some embodiments of the dose determination methods, the
association rate of
the antibody to TL1A (kon-mAb) comprises the association rate of the antibody
to monomeric
TL1A (km-monomer) and association rate of the antibody to trimeric
TL1A(kontrimer), wherein
the dissociation rate of the antibody from TL1A (koff_mAb) comprises the
dissociation rate of
the antibody from monomeric TL1A (koff-monomer) and dissociation rate of the
antibody from
trimeric TL1A olf-trima), and/or wherein the degradation rate of TL1A (k
degtotal-TL1A)
comprises degradation rate of monomeric TL1A (k deg_TL1A-monomer) and
degradation rate of
trimeric TL1A (kdog-TriA-trimer). In some embodiments of the dose
determination methods, the
step (a) comprises receiving association rate of the antibody to FcRn receptor
(k on-mAb-rcRO,
dissociation rate of the antibody from FcRn (koff-mAb-rcRn), association rate
of the antibody-
TL 1 A complex to FcRn receptor (koõ-(m 4)b-TL 1 A)-FcRn), and/or dissociation
rate of the antibody -
TL1A complex from FcRn (k0ff-(mAb-TL1A)-FcRO =
100581 In some embodiments of the dose determination methods, the
association rate of
the antibody- TL1A complex to FcRn receptor (kon-(mAb-TL1A)-Fc10 comprises
association rate
of the antibody -monomeric-TL1A complex to FcRn receptor (kon-(mAb-monoThl A)-
FcRn) and
association rate of the antibody-trimeric-TL1A complex to FcRn receptor (k0n-
(mAb-MTL1A)-
FcRn), and/or wherein the dissociation rate of the antibody- TL1A complex from
FcRn (koff_
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(mAb -TL1A)-FcRO comprises dissociation rate of the antibody-monomeric-TLI A
complex from
FcRn (koff.(mAb-mono TL 1A)-FcRrl) and dissociation rate of the antibody -
trimeric-TLI A complex
from FcRn (koff-(mAb-ttiTL1A)-FcRn).
[0059] In some embodiments of the dose determination methods, the
step (a) further
comprises receiving clearance rate of FcRn receptor bound by the antibody (IC
deg-mAb-FcRn). In
some embodiments of the dose determination methods, the clearance rate of FcRn
receptor
bound by the antibody (1(deg-mAb-FcRn) further comprises clearance rate of the
antibody to FcRn
bound by the antibody -monomeric-TLI A complex (kdeg-(mAb-mono'1L1A)-FcRn) and
clearance rate
of FcRn receptor bound by the antibody-trimeric-TL1A complex (kdeg-(mAb -
tnTL1A)-FcRn).
[0060] In some embodiments of the dose determination methods, the
diseased tissue
comprises any one or more selected from the group consisting of colon, small
intestine,
rectum, cecum, ileum, spleen, a fibrotic tissue from IBD, other tissues with
IBD pathology,
and other tissues of IBD pathogenesis.
[0061] In some embodiments of the dose determination methods, in
the dose
determination methods, wherein: (1) kon-monomer and kon-ttimer are identical
or different; (2) koff_
monomer and korkiimei are identical or different; (3) kdeg-monomel and
kdeg_trimet are identical or
different; (4) kon-(mAb-monomiA)-FeRn and k0n-(mAb-triTL1A)-FcRn are identical
or different; (5) kon-
mAb-FcRn and k0n-(mAb-monoTL1 A)-FcRn are identical or different; (6) kon-mAb-
FcRn and k0n-(mAb-triTL1 A)-
FcRn are identical or different; (7) koff-(mAb-monoTL1A)-FcRn and koff-(mAb-
triTL1A)-FcRn are identical or
different; (8) koff- mAb -FcRn and k0ff-(mAb-monoTL1A)-FcRn are identical or
different; (9) koff- mAb -FcRn
and k0ff-(mAb-tnTL1A)-FcRn are identical or different; (10) kdeg-(mAb-
monoTL1A)-FcRn and kdeg-(mAb-
trilL1A)-FcRn are identical or different; (11) k deg-mAb -FcRn and kdeg-(mAb-
tri1L1A)-FcRn are identical or
different; (12) kdeg-mAb-FcRn and kdog-(mAb-monomiA)-FcRn are identical or
different; or (13) any
combination of (1) to (12).
[0062] In some embodiments of the dose determination methods, in
the dose
determination methods, wherein kõn_disease i S up to 10, 15, 20, 25, 30,35,
40,45, 50,55, 60,
65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190,
200, or more fold
of ksyn-nonnal =
[0063] In some embodiments of the dose determination methods, the
effective dose
regimen comprises an induction regimen of the anti-TLI A antibody or antigen
binding
fragment. In some embodiments of the dose determination methods, the effective
dose
regimen comprises a maintenance regimen of the anti-TLI A antibody or antigen
binding
fragment. In some embodiments of the dose determination methods, the induction
regimen
and the maintenance regimen are identical. In some embodiments of the dose
determination
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methods, the induction regimen and the maintenance regimen are different. In
some
embodiments of the dose determination methods, the maintenance regimen is
administered
after the induction regimen.
100641 In some embodiments of the dose determination methods, the
diseased tissue in
the subject produces up to 50, 60, 70, 80, 90, 100, or more fold of TL1A
compared to the
corresponding tissue in the control subject during the induction regimen. In
some
embodiments of the dose determination methods, the diseased tissue in the
subject produces
up to 50, 60, 70, 80, 90, 100, or more fold of TL1A compared to the
corresponding tissue in
the control subject within 1, 2, 3, 4, 5, or 6 weeks of start of the induction
regimen. In some
embodiments of the dose determination methods, the diseased tissue in the
subject produces
up to 50, 60, 70, 80, 90, 100, or more fold of TL1A compared to the
corresponding tissue in
the control subject. In some embodiments of the dose determination methods,
the induction
regimen comprises a one-time administration of the anti-TL1A antibody or
antigen binding
fragment. In some embodiments of the dose determination methods, the anti-TL1A
antibody
or antigen binding fragnent is administered at 200 mg/dose, 250 mg/dose, 300
mg/dose, 350
mg/dose, 400 mg/dose, 450 mg/dose, 500 mg/dose, 550 mg/dose, 600 mg/dose, 650
mg/dose,
700 mg/dose, 750 mg/dose, 800 mg/dose, 850 mg/dose, 900 mg/dose, 950 mg/dose,
1000
mg/dose, 1100 mg/dose, 1200 mg/dose, 1250 mg/dose, 1300 mg/dose, 1400 mg/dose,
1500
mg/dose, 1600 mg/dose, 1700 mg/dose, 1750 mg/dose, 1800 mg/dose, 1900 mg/dose,
or
2000 mg/dose.
100651 In some embodiments of the dose determination methods, the
induction regimen
comprises multiple administrations of the anti-TL1A antibody or antigen
binding fragment.
In some embodiments of the dose determination methods, the induction regimen
comprises
administrations of (i) 1000 mg/dose on week 0, 1000 mg/dose on week 2, 1000
mg/dose on
week 6, and 1000 mg/dose on week 10; 00500 mg/dose on week 0, 500 mg/dose on
week 2,
500 mg/dose on week 6, and 500 mg/dose on week 10; (iii) 1000 mg/dose on week
0, 1000
mg/dose on week 2, 1000 mg/dose on week 6, and 500 mg/dose on week 10; (iv)
1000
mg/dose on week 0, 1000 mg/dose on week 2, 500 mg/dose on week 6, and 500
mg/dose on
week 10; or (v) 1000 mg/dose on week 0, 500 mg/dose on week 2, 500 mg/dose on
week 6,
and 500 mg/dose on week 10.
100661 In some embodiments of the dose determination methods, the
induction regimen
comprises administration of 2000, 1950, 1900, 1850, 1800, 1750,1700,
1650,1600, 1550,
1500, 1450, 1400, 1350, 1300, 1250, 1200, 1150, 1100, 1050, 1000, 950, 900,
850, 800, 750,
700, 650, 600,550,500,450,400,350,300,250, or 200 mg/dose. In some embodiments
of
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the dose determination methods, the induction regimen comprises administration
once every
2, 4, 6, or 8 weeks. In some embodiments of the dose determination methods,
the induction
regimen comprises administration once every 2 or 4 weeks for the first 2
administrations and
then once every 2, 4, 6, or 8 weeks for the remaining induction regimen.
100671 In some embodiments of the dose determination methods, the
diseased tissue in
the subject produces up to 10, 15, 20, 25, 30, 35, 40, 45, 50, or more fold of
TL1A compared
to the corresponding tissue in the control subject. In some embodiments of the
dose
determination methods, the diseased tissue in the subject produces up to 10,
15, 20,25, 30,
35, 40, 45, 50, or more fold of TL1A compared to the corresponding tissue in
the control
subject during the maintenance regimen. In some embodiments of the dose
determination
methods, the diseased tissue in the subject produces up to 10, 15, 20,25,
30,35, 40,45, 50, or
more fold of TL1A compared to the corresponding tissue in the control subject
within 1, 2, 3,
4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22,24, 28,32, 36,40, 44,48, or
52 weeks, or longer
of start of the maintenance regimen.
100681 In some embodiments of the dose determination methods, the
maintenance
regimen comprises multiple administrations of the anti -TL1A antibody or
antigen binding
fragment. In some embodiments of the dose determination methods, the
maintenance
regimen comprises administrations of the anti-TL1A antibody or antigen binding
fragment at
(i) 500 mg/dose every 2 weeks, (ii) 400 mg/dose every 2 weeks, (iii) 300
mg/dose every 2
weeks, (iv) 250 mg/dose every 2 weeks, (v) 200 mg/dose every 2 weeks, (vi) 150
mg/dose
every 2 weeks, (vii) 100 mg/dose every 2 weeks, (viii) 50 mg/dose every 2
weeks, (ix) 500
mg/dose every 4 weeks, (x) 400 mg/dose every 4 weeks, (xi) 300 mg/dose every 4
weeks,
(xii) 250 mg/dose every 4 weeks, (xiii) 200 mg/dose every 4 weeks, (xiv) 150
mg/dose every
4 weeks, (xv) 100 mg/dose every 4 weeks, (xvi) 50 mg/dose every 4 weeks,
(xvii) 500
mg/dose every 6 weeks, (xviii) 400 mg/dose every 6 weeks, (xix) 300 mg/dose
every 6
weeks, (xx) 250 mg/dose every 6 weeks, (xxi) 200 mg/dose every 6 weeks, (xxii)
150
mg/dose every 6 weeks, (xxiii) 100 mg/dose every 6 weeks, (xxiv) 50 mg/dose
every 6
weeks, (xxv) 500 mg/dose every 8 weeks, (xxvi) 400 mg/dose every 8 weeks,
(xxvii) 300
mg/dose every 8 weeks, (xxviii) 250 mg/dose every 8 weeks, (xxix) 200 mg/dose
every 8
weeks, (xxx) 150 mg/dose every 8 weeks, (xxxi) 100 mg/dose every 8 weeks, or
(xxxii) 50
mg/dose every 8 weeks.
100691 In some embodiments of the dose determination methods, the
maintenance
regimen comprises administration of the anti-TL1A antibody or antigen binding
fragment at
1000, 950, 900, 850, 800, 750, 700, 650, 600, 550, 500, 450, 400, 350, 300,
250, 200, 150,
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100, or 50 mg/dose. In some embodiments of the dose determination methods, the
maintenance regimen comprises administration of the anti-TLIA antibody or
antigen binding
fragment once every 2, 4, 6, 8, 10, or 12 weeks. In some embodiments of the
dose
determination methods, the maintenance regimen comprises administrations of
the anti-TLIA
antibody or antigen binding fragment at 250 mg/dose every 4 weeks. In some
embodiments
of the dose determination methods, the maintenance regimen comprises
administrations of
the anti-TL1A antibody or antigen binding fragment at 100 mg/dose every 4
weeks. In some
embodiments of the dose determination methods, the maintenance regimen
continues for 4, 6,
8, 10, 12, 14, 16, 18, 20,22, 24, 26, 28,30, 32,34, 36,40, 44,48, or 52 weeks.
100701 In some embodiments of the dose determination methods, the
effective dose
regimen maintains the concentration of TLIA in diseased tissue in the subject
below the
concentration of TL1A in a corresponding tissue in a control subject without
IBD for at least
4 weeks, 8 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months,
9 months,
months, II months, 12 months, 2 years, and longer.
100711 In some embodiments of the dose determination methods, the
step (a) further
comprises receiving the rate of TL1A trim erization (k on-TL 1A-monomet -to
ttimet) and/or rate of
TLIA monomerization (koff-TL1A-trimer-to-monomer).
100721 In some embodiments of the methods provided herein,
including the methods of
use/treatment and the methods of dose determination provided herein, the
concentration of
TLIA is the concentration of free TLIA.
100731 In some embodiments, the anti-TL1A antibody comprises a
heavy chain variable
region comprising: an HCDRI comprising an amino acid sequence set forth by SEQ
ID NO:
1, an HCDR2 comprising an amino acid sequence set forth by any one of SEQ ID
NOS: 2-5,
and an HCDR3 comprising an amino acid sequence set forth by any one of SEQ ID
NOS: 6 -
9; and a light chain variable region comprising an LCDRI comprising an amino
acid
sequence set forth by SEQ ID NO: 10, an LCDR2 comprising an amino acid
sequence set
forth by SEQ ID NO: 11, an LCDR3 comprising an amino acid sequence set forth
by any one
of SEQ ID NOS: 12-15.
100741 In some embodiments, the anti-TLI A antibody comprises, a
heavy chain variable
framework region comprising a human IGHV1-46*02 framework or a modified human
IGHV1-46*02 framework, and a light chain variable framework region comprising
a human
IGKV3-20 framework or a modified human IGKV3-20 framework; wherein the heavy
chain
variable framework region and the light chain variable framework region
collectively
comprise no or fewer than nine amino acid modification(s) from the human IGHV1-
46*02
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framework and the human IGKV3 -20 framework.
[0075] In some embodiments, the anti-TL1A antibody comprises a
heavy chain variable
domain comprising an amino acid sequence at least 96% identical to any one of
SEQ ID
NOS: 101-169, and a light chain variable domain comprising an amino acid
sequence at least
96% identical to any one of SEQ ID NOS: 201-220.
100761 In some embodiments, the anti-TL1A antibody comprises a
heavy chain variable
region comprising SEQ ID NO: 301
XlVQLVQSGAEVKKPGASVKVSCKAS[HCDR1]WVX2QX3PGQGLEWX4G[HCDR2]
RX5TX6TX7DTSTSTX8YX9ELSSLRSEDTAVYYCAR[HCDR3]WGQGTTVTVSS, and a
light chain variable region comprising SEQ ID NO: 303
EIVLTQSPGTLSLSPGERATLSC[LCDR1]WYQQKPGQAPRX10X11IY[LCDR2]GIPDR
FSGSGSGTDFTLTISRLEPEDFAVYYC[LCDR3]FGGGTKLEIK, wherein each of X1 -X11
is independently selected from A, R, N, D, C, Q, E, G, H, I, L, K, M, F, P, S,
T, W, Y, or V,
wherein HCDR1 comprises an amino acid sequence set forth by SEQ ID NO: 1,
HCDR2
comprises an amino acid sequence set forth by any one of SEQ ID NOS: 2-5,
HCDR3
comprises an amino acid sequence set forth by any one of SEQ ID NOS: 6-9,
LCDR1
comprises an amino acid sequence set forth by SEQ ID NO: 10, LCDR2 comprises
an amino
acid sequence set forth by SEQ ID NO: 11, and LCDR3 comprises an amino acid
sequence
set forth by any one of SEQ ID NOS: 12 or 13.
3. BRIEF DESCRIPTION OF THE FIGURES
100771 The patent or application file contains at least one drawing
executed in color.
Copies of this patent or patent application publication with color drawing(s)
will be provided
by the Office upon request and payment of the necessary fee.
100781 Exemplary embodiments are illustrated in referenced figures.
It is intended that
the embodiments and figures disclosed herein are to be considered illustrative
rather than
restrictive.
100791 FIGS. 1A-1C show chromatograms for analytical size exclusion
chromatography
of anti-TL1A antibodies. The large peaks (main peak) correspond to monomeric
fraction.
The percentage of monomeric sample is indicated for each antibody. FIG. IA
shows
chromatographs for antibodies Al 93, A 194, and A 195. FIG. 1B shows
chromatographs for
antibodies A196, A197, and A198. FIG. 1C shows chromatographs for antibodies
A199,
A200, and A201.
100801 FIG. 2 depicts inhibition of interferon gamma in human blood
with anti-TL1A
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antibodies.
[0081] FIG. 3A depicts the comparison between the predicted and
measured viscosity.
FIGS. 3B-3D depict a PLS model demonstrating effect of pH and protein
concentration on
viscosity. FIG. 3B shows a PLS graph (x-axis is pH, y-axis is protein
concentration (mg/ml),
z-axis is viscosity (mPa-s) for the PLS graphs), FIG. 3C shows a model of the
predicted
viscosity (y-axis, mPa-s) versus anti-TL1A antibody concentration (x-axis) in
mg/mL, and
FIG. 3D shows a model of the estimated viscosity (y-axis, mPa-s) versus actual
viscosity (x-
axis, mPa-s). FIG. 3E depicts the effects of pH versus acetate concentration
on viscosity.
FIG. 3F shows the effect of sucrose versus NaCl on viscosity. FIG. 3G depicts
the effect of
Arg-HC1 versus Ly s-HC1 on viscosity. Viscosity units are in mPa-s. The arrow
points to the
region of highest viscosity. The star corresponds to the region of lowest
viscosity.
[0082] FIG. 4A depicts the PLS1 model for the effect on high
molecular weight (EIMW)
aggregates. FIG. 4B depicts the effect of pH versus acetate on aggregation.
FIG. 4C depicts
the effect of sucrose versus NaCl concentration. FIG. 4D depicts the effect of
Arg-HC1
versus Ly s-HC1 on aggregation. FIG. 4E depicts the effect of sucrose
concentration versus
Lys-HC1 concentration.
[0083] FIG. 5A depicts the predicted versus measured loss of main
peak at 2 weeks and
25 C. FIG. 5B depicts the effect of pH and protein concentration on the loss
of main peak in
the CEX profile. FIG. 5C depicts the effect of pH and acetate concentration on
the loss of
main peak in the CEX profile. FIG. 5D depicts the effect of sucrose and NaCl
concentration
on the loss of main peak in the CEX profile. FIG. 5E depicts the effect of Lys-
HC1 and
sucrose concentration on the loss of main peak in the CEX profile.
[0084] FIG. 6A depicts the loss of monomer by SEC with agitation.
FIG. 6B depicts the
loss of monomer by SEC with freeze-thaw.
[0085] FIG. 7A depicts the binding of an anti-TL1A antibody to
cynomolgus and human
TL1A, but not to mouse or rat TL1A. ELISA for each protein was performed at
least three
times. The data from a representative experiment are shown and are mean SD.
Abbreviations: A=absorbance, Ab=antibody, Cyno=cynomolgus, nm=nanometer,
nM=nanomolar. FIG. 7B depicts mean levels of sTL1A increased with increasing
IV doses
of anti-TL1A to cynomolgus monkeys, as measured in an ELISA. Samples were
assayed in
triplicate, on two separate occasions. Data presented are the mean TL1A
concentrations of
three animals per group SD. Samples collected from animals administered
isotype control
antibody are shown in circles, samples collected from animals administered
anti-TL1A are
shown in the triangles and square. Abbreviations: hr=hour, kg=kilogram,
mg=milligram,
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mL=milliliter, ng=nanogam; TLIA=tumor necrosis factor-like cytokine 1A.
[0086] FIG. 8 demonstrates that TL1A drives inflammation and
fibrosis through binding
to DR3.
[0087] FIGS. 9A-9C demonstrates size-exclusion chromatography (SEC)
profiles of
recombinant human TL1A (rhTL I A). Briefly, rhTL1A was labeled with Alexa
fluor 488
(AF488) and spiked into normal human serum (NHS). In FIG. 9A, when injected
alone,
rhTL1A SEC profile shows two peaks on SEC, representing trimeric and monomeric
forms
of TL1A. In FIG. 9B, when rhTL1A is pre-incubated with a control reference
antibody, the
trimeric peak was shifted leftward, indicating a larger complex formation of
the reference
antibody and trimeric rhTL1A. There was no shift in the monomeric peak,
indicating that the
reference antibody only binds to the trimeric rhTL1A. In FIG. 9C, when rhTL1A
is pre-
incubated with A219, both the trimeric and the monomeric rhTL1A peaks were
shifted, thus
indicating that A219 binds both trimeric and monomeric forms of TL A.
[0088] FIG. 10A depicts a whole-body physiologically based
pharmacokinetic (PBPK)
model. FIG. 10B depicts a tissue-level diagram of the integrated whole-body
PBPK model
used to characterize the PK of the monoclonal antibody (mAb), ligand, and
complex between
mAb and ligand.
[0089] FIG. 11A depicts the comparison of the pharmacokinetics of
the mAb as
predicted by the integrated whole-body PBPK (solid curve) with the
pharmacokinetics of the
mAb as observed in normal healthy volunteers (various points with points from
the same
subject shown by the same format), in each case after injection of A219 at the
indicated dose.
FIG. 11B depicts the comparison of the TL1A concentration as predicted by the
integrated
whole-body PBPK with the TL1A concentration as observed in normal healthy
volunteers, in
each case after injection of A219 at the indicated dose.
[0090] FIG. 12A depicts the observed concentration of TLIA in serum
after injecting (i)
an anti-TL1A antibody A219 that binds to both TL1A monomer and trimer (shown
in red, top
of the 2 curves, and the observed data points accompanying such curve) and
(ii) a control
reference anti-TL1A antibody that binds to only TL1A trimer (shown in blue,
bottom of the 2
curves, and the observed data points accompanying such curve). In FIG. 12A,
solid curves
depict the prediction from the model and various dots depict the observations
from subjects
injected with the indicated antibodies. FIG. 12B depicts the predicted total
TL1A
concentration (monomer and trimer, solid curve and the observed data points
accompanying
such curve), the monomer TL concentration (fine dotted line), and the trimer
TL
concentration (coarse dotted line), in each case at the basal level (no
injection of any anti-
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TL1A antibodies). FIG. 12C depicts the serum TL1A concentration in normal
healthy
volunteers (NHV) and UC patients, as predicted by the whole-body PBPK model
(solid lines,
upper line for UC patient and lower line for NHV) and as observed (various
points).
100911 FIGS. 13A-13B demonstrate the fitness of the model. FIG. 13A
depicts the
observed concentration of TL1A in serum of NHVs after injecting an anti-TL1A
antibody
that binds to only TL1A trimer (dots) and the prediction of the model (solid
curve) that fits
the observations at the indicated dose. Q2WX3= every 2 weeks for three times.
FIG. 13B
depicts the observed concentration of TL1A in serum of UC patients after
injecting an anti-
TL1A antibody that binds to only TL1A trimer (dots) and the prediction of the
model (solid
curve) that fits the observations at the indicated dose. Q2WX7= every 2 weeks
for seven
times. FIG. 13C depicts the concentration of TL1A in intestine of NHV (black,
solid, lower
line of the two lines as predicted from the model and the observed data points
accompanying
such line) and the concentration of TL1A in the intestine of UC patient (red,
solid, upper line
of the two lines).
100921 FIGS. 14A-14B depict the baseline concentration of TL1A
based on various
parameters of TL1A production in intestine (14A) and in serum (14B). In FIGS.
14A-14B,
1> would be the baseline in NHV; 25x, 50x, 75x, and 100x indicate various
parameters of
TL over-production in intestine.
100931 FIGS 15A-15V depict the concentration of free soluble TL1A
in tissue as
determined by the whole-body PBPK model according to various parameters of
TL1A
overproduction under various dose regimen of anti-TL1A antibody A219 as
indicated. FIG.
15W depicts the free soluble TL1A in tissue as determined by the whole-body
PBPK model
according to various parameters of TL1A overproduction under the dose regimen
of a
reference anti-TL1A antibody as indicated. FIGS. 15X-15Z depict the comparison
of the
modeled free soluble TL1A concentration in subjects treated with a reference
anti-TL1A
antibody (red, the upper curve of the two curves) or A219 (green, the lower
curve of the two
curves). In FIG. 15W-15Z, reference antibody light chain sequence is SEQ ID
NO: 382,
heavy chain sequence is SEQ ID NO: 383, and the whole-body PBPK model uses a
rapid
equilibrium between the monomeric and trimeric form of TL1A with a continuous
60:40 ratio
of monomer and trimer as observed. The black solid lines in FIGS. 15A-15Z
indicate the
TL1A concentration in the tissue of NHV. Q2W=every 2 weeks. Q4W=every 4 weeks.
SC=subcutaneous. LD=loading dose (the first dose). 4W=week 4. Dl=day 1. W2, 6,
10=week 2, week 6, and week 10. W 2, 4, 6, 10=week 2, week 4, week 6, and week
10.
EOW=every other week. W 4, 8, 12=week 4, week 8, and week 12. W 2, 4, 8,
12=week 2,
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week 4, week 8, and week 12. sTL1A=soluble TL1A.
100941 FIGS 16A-161I depict the goodness of fit plots for A219 with
the population PK
model.
100951 FIG. 17A depicts the visual predictive check for the A219
concentration predicted
from the popPK model against the observed A219 concentration. FIG. 17B depicts
an
induction dose selected in the popPK model to rapidly achieve steady state
concentration.
100961 FIG. 18A depicts the study schema for induction period for
the phase 2 clinical
trial for A219 in UC. FIG. 18B depicts the study schema for open-label
extension period for
the phase 2 clinical trial for A219 in UC.
100971 FIG. 19 depicts the study schema for the phase 2 clinical
trial for A219 in CD
100981 FIG. 20 depicts osmotic pressures at 5 C measured for the
stability of A219
samples of various formulations at TO, 3 and 6 months.
100991 FIG. 21 depicts A219 protein concentration at 5 C measured
for evaluating the
stability of A219 samples of various formulations at TO, 3 and 6 months.
1001001 FIG. 22 depicts pH at 5 C measured for the evaluating the stability
A219 samples
of various formulations at TO, 3 and 6 months.
1001011 FIG. 23A depicts viscosity data for TO and 3M for Formulations 1 to 5
at 25 C;
FIG. 23B depicts viscosity data for TO and 3M for Formulations 6 to 8 at 25 C.
1001021 FIG. 24A depicts monomer contents for formulations at 5 C as measured
by SEC;
FIG. 24B depicts loss of monomer (main peak) per month for the formulations at
5 C as
determined by SEC; FIG. 24C depicts monomer contents for formulations at 25 C
as
measured by SEC; FIG. 24D depicts loss of monomer (main peak) per month for
the
formulations at 5 C as determined by SEC.
1001031 FIG. 25A depicts the relative area (%) of the main peak for
formulations at 5 C as
characterized by cation exchange chromatography; FIG. 25B depicts the loss of
main peak
(Rel. Area (%) per month) for the formulations at 5 C as determined by cation
exchange
chromatography; FIG. 25C depicts the relative area (%) of the main peak for
formulations at
25 C as characterized by cation exchange chromatography; FIG. 25D depicts the
loss of
main peak (Rel. Area (%) per month) for the formulations at 25 C as determined
by cation
exchange chromatography.
1001041 FIG. 26A depicts predicted vs. measured values according to the PLS
model
using monomer loss by SEC for samples stored for 2 months at 25 C as the
endpoint; FIG.
26B depicts effect of pH and protein according to the PLS model using monomer
loss by
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SEC for samples stored for 2 months at 25 C as the endpoint. In FIG. 26B, the
sucrose
concentration was fixed at 200 mM. FIG. 26C depicts effect of pH and acetate
according to
the PLS model using monomer loss by SEC for samples stored for 2 months at 25
C as the
endpoint. In FIG. 26C, the sucrose concentration was fixed at 200 mM. FIG. 26D
depicts
effect of sucrose and lysine according to the PLS model using monomer loss by
SEC for
samples stored for 2 months at 25 C as the endpoint. In FIG. 26D, the protein
concentration
was fixed at 150 mg/mL, pH at 5.5 and acetate at 20 mM. FIG. 26E depicts
effect of glycine
and NaC1 according to the PLS model using monomer loss by SEC for samples
stored for 2
months at 25 C as the endpoint. In FIG. 26E, the protein concentration was
fixed at 150
mg/mL, pH at 5.5 and acetate at 20 mM.
1001051 In FIGs. 20, 21, 22, 23A-23B, 24A-240, 25A-25D, and 26A-26E, the
formulations 1-8 (F01-F08, Form. 1-8, or simply 1-8) referenced therein are
the formulations
1-8 as described in Table 31 of Example 24.
1001061 FIG. 27A shows geometric mean serum A219 concentration-time profiles
following single doses of A219 administered as IV infusion (Linear Scale) (SAD
study).
FIG. 27B shows geometric mean serum A219 concentration-time profiles following
multiple
doses of A219 Q2W administered as IV infusion - day 29 (linear scale) (MAD
study).
Q2W=every 2 weeks.
1001071 FIG. 28A shows geometric mean serum sTL1A concentration versus nominal
time following single dose of A219 administered as IV Infusion (semi-log
scale) (SAD
study). FIG. 28B geometric mean serum sTL1A concentration versus nominal time
following multiple doses of A219 Q2W administered as IV infusion (semi-log
scale) (MAD
study).
1001081 FIG. 29A shows total A219 concentration in the central compartment (in
circulation) in SAD as predicted by the model (curves) and as determined in
the phase I trial
(dots). FIG. 29B shows total soluble TL1A in the central compartment
(circulation) in SAD
as predicted by the model (curves) and as determined in the phase I trial.
FIG. 29C shows
total A219 concentration in the central compartment (in circulation) in MAD as
predicted by
the model (curves) and as determined in the phase I trial (dots). FIG. 29D
shows total
soluble TL I A in the central compartment (circulation) in MAD as predicted by
the model
(curves) and as determined in the phase I trial (dots). The predicted curves
fitted with the
measured data points. FIGS. 29E-29K show model prediction for and the data of
a control
reference antibody that binds only to TL1A trimer (light chain SEQ ID NO: 382
and heavy
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chain SEQ ID NO: 383) with regard to (1) phase I single ascending dose data
(FIGS. 29E
and 29F), (2) phase I multiple ascending dose data (FIGS. 29G and 291I), and
(3) phase II
data on PK & total sTL1A levels (FIGS. 291 and 29J). The IBD specific
parameters were
then calibrated to capture free tissue TL1A levels in the gut (FIG. 29K) as
observed with the
control reference antibody (light chain SEQ ID NO: 382 and heavy chain SEQ ID
NO: 383).
NR=non-responder and R=responder.
1001091 FIG. 30A shows doses of A219 determined from the validated model that
can
bring the free TL1A concentration in the patient's diseased tissue to below
the TL1A
concentration of a healthy subject. FIG. 30B shows the percent reduction of
the free TL1A
in the diseased tissue after administering doses of A219 as determined from
the model.
IV 4x= 1000 mg loading dose, 3 x 500 mg on days 14, 42, 70. SC dosing 240 mg
Q1W or
Q2W. FIG. 30C shows that, in a head-to-head comparison in the validated model,
anti-
TL1A antibodies that bind to both TL1A monomer and trimer engaged more (3.5
fold more)
TL1A in circulation than anti-TL1A antibodies that only bind to TL1A trimer.
FIG. 30D
shows that, in a head-to-head comparison in the validated model, anti-TL1A
antibodies that
bind to both TL1A monomer and trimer also resulted in higher percentage of
TL1A reduction
of TL1A in diseased tissue (about 100%) when compared to anti-TL1A antibodies
that only
bind to TL1A trimer.
1001101 FIG. 31A shows the diagram of a popPK model. FIG. 31B shows the
comparison of the A219 concentration predicted from the popPK model and the
A219
concentration observed in the population of subjects in phase I clinical trial
via a linear
regression plot. FIG. 31C shows the comparison of the TL1A concentration
predicted from
the popPK model and the TL1A concentration ob served in the population of
subjects in phase
clinical trial via a linear regression plot. FIG. 310 shows the comparison of
the A219
concentration predicted from the popPK model and the A219 concentration
observed in the
population of subjects in phase I clinical trial via a time series plot. FIG.
31E shows the
comparison of the TL1A concentration predicted from the popPK model and the
TL1 A
concentration observed in the population of subjects in phase I clinical trial
via a time series
plot.
1001111 FIGS. 32A-32H show the A219 and TL1A engagement (TL1A concentration in
serum) predicted from the validated popPK model under various A219 doses.
FIGS. 32A
and 32B show A219 concentration (32A) and TL1A concentration (32B) in
circulation with a
dosing regimen of induction with 500 mg Q2W (6 doses) up to week 10 and
extension with
500 mg Q2W from week 12 to week 52 (20 doses). FIGS. 32C and 32D show A219
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concentration (32C) and TL1A concentration (32D) in circulation with a dosing
regimen of
induction with 500 mg Q2W (6 doses) up to week 10 and extension with 500 mg
Q4W from
week 12 to week 52 (10 doses). FIGS. 32E and 32F show A219 concentration (32E)
and
TL1A concentration (32F) in circulation with a dosing regimen of induction
with 500 mg
Q2W (6 doses) up to week 10 and extension with 100 mg Q2W from week 12 to week
52 (20
doses). FIGS. 32G and 32H show A219 concentration (32G) and TL1A concentration
(32H) with a dosing reOmen of induction with 500 mg Q2W (6 doses) up to week
10 and
extension with 250 mg Q4W from week 12 to week 52 (10 doses).
4. DESCRIPTION OF THE INVENTION
1001121 TL1A is a cytokine that is secreted by antigen-presenting
cells, T cells, and
endothelial cells. 'TL1A signals through death receptor 3 (DR3), a 'TNF-family
receptor that is
found primarily on T cells, natural killer (NK) and NK-T cells, innate
lymphoid cells (ILC),
fibroblasts, and epithelial cells and potently drives Thl, Th2, Th9 and Th17
responses. In
addition, it is induced in antigen-presenting cells by toll like receptor
(TLR) ligands and FcR
cross-linking and in T cells by T cell receptor (TCR) stimulation.
[00113] FIG. 8 demonstrates how TL1A binding to DR3 independently drives
inflammation and fibrosis. TL1A binding to DR3 on innate and T cells leads to
an early
cytokine response (release of IL-23, IL-113, IL-17, IL-22, TNF-a, IFN-y, IL-
13) that sets the
stage for inflammation, and stimulates innate and adaptive immune response.
For instance,
through binding to DR3, TL1A potentially drives inflammatory Thl and Th17
responses.
Further, binding of TL1A to DR3 on fibroblasts directly activates fibroblasts,
and leads to
collagen disposition and fibrosis independent of inflammation. While levels of
circulating
TL IA are low in healthy subjects, they are elevated in patients suffering
from many auto-
immune diseases, and TL1A has been shown to be upregulated in mucosa and serum
of
patients with IBD. In mice, chronic TL1A expression causes structuring disease
caused by
increased collagen deposition. In dextran sodium sulfate (DSS) and adoptive
transfer mouse
models, when challenged with DSS, TL1A transgenic mice develop more severe
colitis than
wild-type animals, and antibodies against TL1A led to reduced inflammation,
lowered
collagen levels, and reversal of fibrosis, even when treatment was
administered late in the
course of disease, after inflammation and fibrosis has been established
Furthermore, TL1A
polymorphisms have been shown to be associated with susceptibility to IBD and
with disease
severity.
1001141 Fibrosis is a significant clinical phenotype exhibited by
IBD patients. Seventy
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percent of Crohn's disease (CD) patients develop stricture/perforation, and
stricture is the
leading indication for surgery in CD. Unfortunately, anti-inflammatory agent
use over the
past decade has not materially changed the rate of structuring disease or need
for surgery.
Further, in ulcerative colitis (UC), subclinical fibrosis has significant
implications on patient
symptoms. For instance, subclinical fibrosis could contribute to symptoms of
diarrhea,
abdominal pain, urgency, and incontinence. Subclinical fibrosis is also the
potential
explanation for persistent symptoms after resolution of inflammation. In
addition, a
Cleveland Clinic study of 89 consecutive colectomy specimens revealed
submucosal fibrosis
in 100% of the specimens. Thus, treatment of fibrosis constitutes an unmet
need in IBD.
1001151 The potential for TL1A as a therapeutic target in
intestinal fibrosis has been
demonstrated in a study evaluating the effect of anti-TL1A antibodies in mouse
models of
IBD. In these studies, two mouse models of chronic colitis were utilized:
adoptive T cell
transfer and chronic DSS. In both models, a neutralizing TL1A monoclonal
antibody (mAb)
or an isotype control antibody was administered two times per week in mice (T
cell transfer
n=14; DSS n=28) with an established colitis. In both disease models, treatment
with the
TL1A mAb reduced colonic collagen deposition levels back to those seen in
healthy control
mice, suggesting that blocking TL1A signaling not only prevented progression
of colonic
fibrosis, but also reversed established fibrosis to similar levels measured
prior to the onset of
inflammation. This data indicates that intestinal fibrosis mediated by
increased levels of
TL1A may be treated with an anti-TL1A antibody.
1001161 In one aspect, provided herein are humanized monoclonal antibodies
that bind to
both membrane-bound and soluble forms of TL1A with high affinity and
specificity and
block the binding of TL1A to its functional receptor DR3. By targeting both
inflammation
and fibrosis, such antibodies have the potential to improve outcomes for IBD
patients, such as
those with increased TL1A expression.
1001171 The term "and/or" as used in a phrase with a list of members is
intended to include
all members individually and all combination of full or partial list of
members. For example,
a phrase such as "A and/or B" herein is intended to include both A and B; A or
B; A (alone);
and B (alone). Likewise, the term "and/or" as used in a phrase such as "A, B,
and/or C" is
intended to encompass each of the following embodiments: A, B, and C; A, B, or
C; A or C;
A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C
(alone).
4.1 General Techniques
1001181 Techniques and procedures described or referenced herein include those
that are
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generally well understood and/or commonly employed using conventional
methodology by
those skilled in the art, such as, for example, the widely utilized
methodologies described in
Sambrook et al., Molecular Cloning: A Laboratory Manual (3d ed. 2001); Current
Protocols
in Molecular Biology (Ausubel et a/. eds., 2003); Therapeutic Monoclonal
Antibodies: From
Bench to Clinic (An ed. 2009); Monoclonal Antibodies: Methods and Protocols
(Albitar ed.
2010); and Antibody Engineering Vols 1 and 2 (Kontermann and Dith el eds., 2d
ed. 2010).
4.2 Anti-TL1A Antibodies
[00119] TT,1A exists in both monomeric and trimeric form in vivo
and in vitro The
disclosure provides that although the trimeric form is the biologically active
form that can
bind to the physiological receptor, death receptor 3 ("DR3") and trigger TL1A
mediated
signaling (e.g. Zhan, C et al., Structure 19: 162-171(2011)), monomeric TL1A
accounts for a
large fraction of the TL1A pool in a subject. By one of the inventors'
estimates, the
monomeric TL1A can be 60% of the total TL1A in the circulating blood. The term
"total
TL1A" refers to both monomeric and trimeric TL1A. The disclosure further
provides that,
despite monomeric TL being biologically inactive, anti-TL1A antibodies binding
to both
monomeric and trimeric TL1A provide advantages over antibodies binding to only
trimeric
TL1A. As provided herein and further demonstrated in Section 5, such
advantages include
more efficient reduction of the TL1A concentration in a diseased tissue in a
subject including
the concentration trimeric TL1A in the diseased tissue, more efficient
reduction of the TL1A
concentration in the blood in a subject including the concentration trimeric
TL1A in the
blood, more sustained reduction of TL concentration (including trimeric
TLIA
concentration) in a diseased tissue in a subject, and/or more sustained
reduction of TL1A
concentration (including trimeric TL1A concentration) in the blood in a
subject.
[00120] In one aspect, provided herein are antibodies or antigen binding
fragments thereof
that bind to tumor necrosis factor-like protein lA ("TL1A," and such antibody
or antigen
binding fragment thereof, "anti-TL1A antibody or antigen binding fragment" or
"anti-TL1A
antibody(ies)" in the specification for simplicity), wherein the antibodies or
antigen binding
fragments bind to both monomeric TL1A and trimeric TL1A. Further embodiments
of the
anti-TL1A antibodies, including embodiments with exemplary CDRs, framework
sequences,
constant region sequences, Fc mutations, variable regions, Fc regions, and
other properties
are further provided in this Section (Section 4.2). Assays for screening,
testing, and
validating the anti-TL1A antibodies are provided in Section 4.3. Methods for
generating,
improving, mutating, cloning, expressing, and isolating the anti-TL1A
antibodies are
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provided in Section 4.4. Pharmaceutical compositions for the anti-TL1A
antibodies are
described and provided in Section 4.5. Methods of using the anti-TL1A
antibodies are
provided in Section 4.6. Further specific and validated embodiments for the
anti-TL1A
antibodies and the methods of using the same are provided in Section 5. As
such, the
disclosure provides the various combinations of the anti-TL1A antibodies, the
pharmaceutical
compositions of such anti-TL1A antibodies, the methods of generating the anti-
TL1A
antibodies, the methods of assaying the anti-TL1A antibodies, and the methods
of using the
anti-TL1A antibodies for treatment.
1001211 In one embodiment of the various anti-TL1A antibodies or antigen
binding
fragments thereof provided herein, the antibody or antigen binding fragment
blocks binding
of TL1A to Death Receptor 3 ("DR3"). In another embodiment, the antibody or
antigen
binding fragment blocks the binding of trimeric TL1A to DR3. In a further
embodiment, the
antibody or antigen binding fragment blocks the signaling DR3 signaling
mediated by TL1A
In yet another embodiment, the antibody or antigen binding fragment blocks the
increase of
IFNy secretion by various immune cells. In a specific embodiment, the antibody
or antigen
binding fragment blocks the increase of IFNy secretion by peripheral blood
mononuclear
cells, including various B cells, T cells, natural killer cells, and/or
macrophages.
1001221 As described herein, the disclosure provides anti-TL1A antibodies or
antigen
binding fragments for binding both monomeric and trimeric TL1A. Therefore, in
one
embodiment of the various anti-TL1A antibodies or antigen binding fragments
thereof
provided herein, binding affinity of the antibody or antigen binding fragment
to monomeric
TL1A as measured by dissociation equilibrium constant (K-monomer) is
comparable to binding
affinity of the antibody or antigen binding fragment to trimeric TL1A as
measured by
dissociation equilibrium constant (Kp_tiimer). Such KD_monomer and/or KDtrim,
can be
determined via any of the methods known and practice by a skilled artisan in
the field and via
any of the applicable assays and methods described herein, including in this
Section (Section
4.2) and Section 5.
1001231 The terms "binds" or "binding" refer to an interaction between
molecules
including, for example, to form a complex. Interactions can be, for example,
non-covalent
interactions including hydrogen bonds, ionic bonds, hydrophobic interactions,
and/or van der
Waals interactions. A complex can also include the binding of two or more
molecules held
together by covalent or non-covalent bonds, interactions, or forces. The
strength of the total
non-covalent interactions between a single antigen-binding site on an antibody
and a single
epitope of a target molecule, such as TL I A, is the affinity of the antibody
or functional
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fragment for that epitope. The ratio of dissociation rate (koff) to
association rate (k011) of an
antibody to a monovalent antigen (koff/kon) is the dissociation constant Kip,
which is inversely
related to affinity. The lower the KD value, the higher the affinity of the
antibody. The value
of KD varies for different complexes of antibody and antigen and depends on
both k0n and
koff. The dissociation constant KD for an antibody provided herein can be
determined using
any method provided herein or any other method well known to those skilled in
the art. The
affinity at one binding site does not always reflect the true strength of the
interaction between
an antibody and an antigen. When complex antigens containing multiple,
repeating antigenic
determinants, such as a polyvalent TL IA trimer, come in contact with
antibodies containing
multiple binding sites, the interaction of antibody with antigen at one site
will increase the
probability of a reaction at a second site. The strength of such multiple
interactions between
a multivalent antibody and antigen is called the avidity. The avidity of an
antibody can be a
better measure of its binding capacity than is the affinity of its individual
binding sites.
1001241 "Binding affinity" generally refers to the strength of the sum total
of noncovalent
interactions between a single binding site of a molecule (e.g., a binding
protein such as an
antibody) and its binding partner (e.g, an antigen). Unless indicated
otherwise, as used
herein, "binding affinity" refers to intrinsic binding affinity which reflects
a 1:1 interaction
between members of a binding pair (e.g., antibody and antigen). As described
above, the
affinity of a binding molecule X for its binding partner Y can generally be
represented by the
dissociation constant (KD). Affinity can be measured by common methods known
in the art,
including those described herein. Low-affinity antibodies generally bind
antigen slowly and
tend to dissociate readily, whereas high-affinity antibodies generally bind
antigen faster and
tend to remain bound longer. A variety of methods of measuring binding
affinity are known
in the art, any of which can be used for purposes of the present disclosure.
Specific
illustrative embodiments include the following. In one embodiment, the "KD" or
"KD value"
can be measured by assays known in the art, for example by a binding assay.
The KD can be
measured in a RIA, for example, performed with the Fab version of an antibody
of interest
and its antigen (Chen et al., 1999, J. Mol Biol 293:865-81). The KD or KD
value can also be
measured by using surface plasmon resonance assays by Biacore , using, for
example, a
Biacore TM-2000 or a Biacore TM-3000, or by biolayer interferometry using, for
example,
the OcterQK384 system. An "on-rate" or "rate of association" or "association
rate" or "lc."
can also be determined with the same surface plasmon resonance or biolayer
interferometry
techniques described above using, for example, a Biacore(')TM-2000 or a
BiacoreTM-3000,
or the Octee'QK3 84 system.
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1001251 Accordingly, the relative binding affinity of the anti-TL1A antibody
or antigen
binding fragment for the TL1A monomer and TL1A trimer can be described and
provided by
KD-monomer and KD-trimer. In one embodiment of the various anti-TL1A
antibodies or antigen
binding fragments provided herein, the KD-monomer is within 1.5, 2, 3, 4, 5,
6, 7, 8, 9, or 10 fold
of the KD-trimer. In another embodiment of the various anti-TL1A antibodies or
antigen
binding fragments provided herein, the KD-monomer is within 10%, 20%, 30%,
40%, or 50% of
the KD-tnmet- In a further embodiment of the various anti-TL1A antibodies or
antigen binding
fragments provided herein, the Kll-trimer is within 1.5, 2, 3, 4, 5, 6, 7, 8,
9, or 10 fold of the KD-
monomer- In another embodiment of the various anti-TL1A antibodies or antigen
binding
fragments provided herein, the KD-tomer is within 10%, 20%, 30%, 40%, or 50%
of the KD_
monomer-
1001261 More specifically, in one embodiment of the various anti-TL1A
antibodies or
antigen binding fragments provided herein, KD-monomer is at most 5 x10-12 M,
at most 6 xl 0-12
M, at most 7x10-12 M, at most 8x10-12M, atmost9x10-12M, at most 1 x10-"M, at
most
2x10-11m, at most 3 x 041 m, at most 4 xio-n m, at most 5x10-11M, at most 6x10-
11M, at
most 7x10-11M, at most 8x10-11M, at most 9x10-11M, at most 1 x10-1 M, at most
2x to-to m,
at most 3 x10-1 M, at most 4 x10-10 m, atmost5x10-1 M, at most 6x10-1 M, at
most 7x10-1
M, at most 8 x10-1 M, at most 9 x10-1 M, or at most 1 x10-9M. In another
embodiment, Kip_
monomer is about 5>(1012 M, about 6 x10-12M, about 7x10-12M, about 8x1 0-12M,
about 9x10-12
M, about 1 x10-"M, about 2x10-" M, about 3 x10-"M, about4x10-" M, about 5x10-"
M,
about 6x10-itm, about7x10-ttm, about 8x10" M, about 9 x10-11 M, about 1x10'
M, about
2x10-1 M, about 3x10-1 M, about 4x10-1 M, about 5x10-1 M, about 6x10-1 M,
about 7x10-
m,
about 8x10' M, about 9 x10-1 M, or about 1 x10 -9M. In a further embodiment
of the
various anti-TL1A antibodies or antigen binding fragments provided herein, KD-
trimer is at
most 5><10'2M, at most 6x10-12M, at most 7x10-12M, atmost8x10-12M, at most
9x10-12m,
at most 1 x10-11M, at most 2 x10-11M, at most 3 x1011 M, at most 4 x10-11M, at
most 5x101'
M, at most 6x10-11M, at most 7x10-11M, at most 8 x10-11 M, at most 9x10-11M,
at most
1 x 0-10 M, at most 2x ci-to m, at most 3 x10-10 m, at most 4x10-1 M, at most
5 x10-1 M, at
most 6x 0-to m, at most 7x10-1 M, at most 8x10' M, at most 9x10-1 M, or at
most 1x109
M. In yet another embodiment, KD-tnmet is about 5 x10-12 M, about 6 x1042 M,
about 7 x1042
M, about 8x10-12M, about 9x10-12M, about 1 x10-11 M, about 2 x10-11 M, about 3
x10-11M,
about 4x10-11M, about 510" M, about 6x10-" M, about 7x10-11M, about 8x10-11M,
about
9><1011M, about 1 x10-1 M, about 2x10-1 M, about 3x10-1 M, about 4x10-1 M,
about 5x10-
10 M, about 6x10-1 M, about 7x10-1 M, about 8x10-1 M, about 9x10-1 M, or
about 1 x10-9
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M. The disclosure further provides that the KD-monomei and KD-trimet can be
any combination of
the KD,õ,)õ1, and Kip_trimer value or range as provided herein, including in
this Section
(Section 4.2) and this paragraph.
1001271 In a further specific embodiment, the KD-monomer is about 59 pM. In
another
specific embodiment, the KD-trimer is about 59 pM. In a further embodiment,
the KD-monomer is
about 59 pM and the Kfl_trimer is about 59 pM. In one specific embodiment, the
Knmonomer is
about 60 pM. In another specific embodiment, the KD-tnmei is about 60 pM. In a
further
embodiment, the Kll-monomer is about 60 pM and the KD-tnmer is about 60 pM. In
one specific
embodiment, the KD-monomer is at most 60 pM. In another specific embodiment,
the KD-trimer is
at most 60 pM. In a further embodiment, the KD-monomer is at most 60 pM and
the KD-trimer is at
most 60 pM.
1001281 In one aspect, provided herein are antibodies that bind to TL1A. In
some
embodiments, an antibody comprises an antigen-binding fragment that refers to
a portion of
an antibody having antigenic determining variable regions of an antibody.
Examples of
antigen-binding fragments include, but are not limited to Fab, Fab', F(ab')2,
and Fv
fragments, linear antibodies, single chain antibodies, and multi specific
antibodies formed
from antibody fragments. In some embodiments, an antibody refers to an
immunoglobulin
molecule that recognizes and specifically binds to a target, such as a
protein, polypeptide,
peptide, carbohydrate, polynucleotide, lipid, or combinations of the foregoing
through at least
one antigen recognition site within the variable region of the immunoglobulin
molecule. In
some embodiments, an antibody includes intact polyclonal antibodies, intact
monoclonal
antibodies, antibody fragments (such as Fab, Fab', F(ab')2, and Fv fragments),
single chain
Fv (scFv) mutants, a CDR-grafted antibody, multispecific antibodies, chimeric
antibodies,
humanized antibodies, human antibodies, fusion proteins comprising an antigen
determination portion of an antibody, and any other modified immunoglobulin
molecule
comprising an antigen recognition site so long as the antibodies exhibit the
desired biological
activity. An antibody can be of any the five major classes of immunoglobulins:
IgA, IgD,
IE5F, IgG, and IgM, or subclasses (isotypes) thereof (e.g., IgGI, IgG2, IgG3,
IgG4, IgAl and
IgA2), based on the identity of their heavy-chain constant domains referred to
as alpha, delta,
epsilon, gamma, and mu, respectively. The different classes of immunoglobulins
have
different and well-known subunit structures and three-dimensional
configurations. Antibodies
can be naked or conjugated to other molecules such as toxins, radioisotopes,
etc.
1001291 In some embodiments, a humanized antibody refers to forms of non-human
(e.g.,
murine) antibodies having specific immunoglobulin chains, chimeric
immunoglobulins, or
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fragments thereof that contain minimal non-human (e.g., murine) sequences. In
a non-
limiting example, a humanized antibody comprises less than about 40% non-human
sequence
in the variable region. In some cases, a humanized antibody comprises less
than about 20%
non-human sequence in a full-length antibody sequence. In a further non-
limiting example, a
humanized antibody comprises less than about 20% non-human sequence in the
framework
region of each of the heavy chain and light chain variable regions. For
instance, the
humanized antibody comprises less than about 20%, 19%, 18%, 17%, 16%, 15%,
14%, 13%,
12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% non-human sequence in the
framework region of each of the heavy chain and light chain variable regions.
As another
example, the humanized antibody comprises about or less than about 15, 14, 13,
12, 11, 10, 9,
8, 7, 6, 5, 4, 3, 2, or 1 non-human sequences in the framework region of each
of the heavy
chain and light chain variable regions. In some cases, humanized antibodies
are human
immunoglobulins in which residues from the complementarity determining region
(CDR) are
replaced by residues from the CDR of a non-human species (e.g., mouse, rat,
rabbit, hamster)
that have the desired specificity, affinity, and capability. These humanized
antibodies may
contain one or more non-human species mutations, e.g., the heavy chain
comprises about 1,
2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 non-human species mutations
in the framework
region, and the light chain comprises about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
12,13, 14, or 15
non-human species mutations in the framework region. The humanized heavy chain
variable
domain may comprise IGHV1-46*02 framework with no or fewer than about 10,9, 8,
7, 6, 5,
4, 3, 2, or 1 amino acid mutations. The humanized light chain variable domain
may comprise
IGKV3-20 framework with no or fewer than about 10, 9, 8, 7, 6, 5, 4, 3, 2, or
1 amino acid
mutations.
1001301 In some embodiments, chimeric antibodies refer to antibodies
wherein the
sequence of the immunoglobulin molecule is derived from two or more species.
As a non -
limiting example, the variable region of both light and heavy chains
corresponds to the
variable region of antibodies derived from one species of mammals (e.g.,
mouse, rat, rabbit,
etc.) with the desired specificity, affinity, and capability while the
constant regions are
homologous to the sequences in antibodies derived from another (usually human)
to avoid
eliciting an immune response in that species.
1001311 The terms "complementarity determining region," and "CDR," which are
synonymous with "hypervariable region" or "HVR," are known in the art to refer
to non-
contiguous sequences of amino acids within antibody variable regions, which
confer antigen
specificity and/or binding affinity. In general, there are three CDRs in each
heavy chain
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variable region (CDR-H1, CDR-H2, CDR-H3) and three CDRs in each light chain
variable
region (CDR-L1, CDR-L2, CDR-L3). "Framework regions" and "FR" are known in the
art to
refer to the non-CDR portions of the variable regions of the heavy and light
chains. In
general, there are four FRs in each full-length heavy chain variable region
(FR-H1, FR-H2,
FR-H3, and FR-H4), and four FRs in each full-length light chain variable
region (FR-L1, FR-
L2, FR-L3, and FR-L4). The precise amino acid sequence boundaries of a given
CDR or FR
can be readily determined using any of a number of well-known schemes,
including those
described by Kabat et al. (1991), "Sequences of Proteins of Immunological
Interest," 5th Ed.
Public Health Service, National Institutes of Health, Bethesda, MD ("Kabat"
numbering
scheme), Al-Lazikani et al., (1997) JMB 273,927-948 ("Chothia" numbering
scheme);
MacCallum et al., J. Mol. Biol. 262:732-745 (1996), "Antibody-antigen
interactions: Contact
analysis and binding site topography," J. Mol. Biol. 262, 732-745." ("Contact"
numbering
scheme); Lefranc MP et al.,"IMGT unique numbering for immunoglobulin and T
cell
receptor variable domains and Ig superfamily V-like domains," Dev Comp
Inummol, 2003
Jan;27(1):5 5 -77 ("IMGT" numbering scheme); Honegger A and Phickthun A, "Yet
another
numbering scheme for immunoglobulin variable domains: an automatic modeling
and
analysis tool," J Mol Biol, 2001 Jun 8;309(3):657-70, ("Aho" numbering
scheme); and
Whitelegg NR and Rees AR, "WAM: an improved algorithm for modelling antibodies
on the
WEB," Protein Eng. 2000 Dec;13(12):819-24 ("AbM" numbering scheme. In certain
embodiments, the CDRs of the antibodies described herein can be defined by a
method
selected from Kabat, Chothia, EVIGT, Aho, AbM, or combinations thereof.
[00132] In some embodiments, an antibody that specifically binds to a protein
indicates
that the antibody reacts or associates more frequently, more rapidly, with
greater duration,
with greater affinity, or with some combination of the above to the protein
than with
alternative substances, including unrelated proteins.
[00133] In some embodiments, the terms "polypeptide," "peptide," and "protein"
are used
interchangeably herein to refer to polymers of amino acids of any length. The
polymer may
be linear or branched, it may comprise modified amino acids, and it may be
interrupted by
non-amino acids. The terms also encompass an amino acid polymer that has been
modified
naturally or by intervention; for example, disulfide bond formation,
glycosylation, lipidation,
acetylation, phosphorylation, or any other manipulation or modification, such
as fusion with
another polypeptide and/or conjugation, e.g., with a labeling component. Also
included
within the definition are, for example, polypeptides containing one or more
analogs of an
amino acid (for example, unnatural amino acids, etc.), as well as other
modifications known
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in the art.
1001341 In some embodiments, a protein such as an antibody described herein
comprises a
hydrophobic amino acid. Non-limiting exemplary hydrophobic amino acids include
glycine
(Gly), proline (Pro), phenylalanine (Phe), alanine (Ala), isoleucine (Ile),
leucine (Leu), and
valine (Val). In some embodiments, a protein such as an antibody described
herein comprises
a hydrophilic amino acid. Non-limiting exemplary hydrophilic amino acids
include serine
(Ser), threonine (Thr), aspartic acid (Asp), glutamic acid (Glu), cysteine
(Cys), asparagine
(Asn), glutamine (Gin), arginine (Arg), and histidine (His). In some
embodiments, a protein
such as an antibody described herein comprises an amphipathic amino acid. Non-
limiting
exemplary amphipathic amino acids include lysine (Lys), tryptophan (Trp),
tyrosine (Tyr),
and methionine (Met). In some embodiments, a protein such as an antibody
described herein
comprises an aliphatic amino acid. Non-limiting exemplary aliphatic amino
acids include
alanine (Ala), isoleucine (Ile), leucine (Leu) and valine (Val). In some
embodiments, a
protein such as an antibody described herein comprises an aromatic amino acid.
Non-limiting
exemplary aromatic amino acids include phenylalanine (Phe), tryptophan (Trp),
and tyrosine
(Tyr). In some embodiments, a protein such as an antibody described herein
comprises an
acidic amino acid. Non-limiting exemplary acidic amino acids include aspartic
acid (Asp)
and glutamic acid (Glu). In some embodiments, a protein such as an antibody
described
herein comprises a basic amino acid. Non-limiting exemplary basic amino acids
include
arginine (Arg), histidine (His), and lysine (Lys). In some embodiments, a
protein such as an
antibody described herein comprises a hydroxylic amino acid. Non-limiting
exemplary
hydroxylic amino acids include serine (Ser) and threonine (Thr). In some
embodiments, a
protein such as an antibody described herein comprises a sulfur-containing
amino acid. Non-
limiting exemplary sulfur-containing amino acids include cysteine (Cys) and
methionine
(Met). In some embodiments, a protein such as an antibody described herein
comprises an
amidic amino acid. Non-limiting exemplary amidic amino acids include
asparagine (Asn) and
glutamine (Gin).
1001351 In some embodiments, "polynucleotide," or "nucleic acid," as used
interchangeably herein, refer to polymers of nucleotides of any length, and
include DNA and
RNA. The nucleotides can be deoxyribonucleotides, ribonucleotides, modified
nucleotides or
bases, and/or their analogs, or any substrate that can be incorporated into a
polymer by DNA
or RNA polymerase. A polynucleotide may comprise modified nucleotides, such
as, but not
limited to methylated nucleotides and their analogs or non-nucleotide
components.
Modifications to the nucleotide structure may be imparted before or after
assembly of the
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polymer. A polynucleotide may be further modified after polymerization, such
as by
conjugation with a labeling component.
[00136] Percent (%) sequence identity with respect to a reference polypeptide
sequence is
the percentage of amino acid residues in a candidate sequence that are
identical with the
amino acid residues in the reference polypeptide sequence, after aligning the
sequences and
introducing gaps, if necessary, to achieve the maximum percent sequence
identity, and not
considering any conservative substitutions as part of the sequence identity.
Alignment for
purposes of determining percent amino acid sequence identity can be achieved
in various
ways that are known for instance, using publicly available computer software
such as
BLAST, BLAST-2, ALIGN or MegaHD) (DNASTAR) software. Appropriate parameters
for
aligning sequences are able to be determined, including algorithms needed to
achieve
maximal alignment over the full length of the sequences being compared. For
purposes
herein, however, % amino acid sequence identity values are generated using the
sequence
comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer
program was authored by Genentech, Inc., and the source code has been filed
with user
documentation in the U.S. Copyright Office, Washington D.C., 20559, where it
is registered
under U.S. Copyright Registration No. TXU510087. The ALIGN-2 program is
publicly
available from Genentech, Inc., South San Francisco, Calif., or may be
compiled from the
source code. The ALIGN-2 program should be compiled for use on a UNIX
operating
system, including digital UNIX V4.0D. All sequence comparison parameters are
set by the
ALIGN-2 program and do not vary.
[00137] In situations where ALIGN-2 is employed for amino acid sequence
comparisons,
the % amino acid sequence identity of a given amino acid sequence A to, with,
or against a
given amino acid sequence B (which can alternatively be phrased as a given
amino acid
sequence A that has or comprises a certain % amino acid sequence identity to,
with, or
against a given amino acid sequence B) is calculated as follows: 100 times the
fraction X/Y,
where X is the number of amino acid residues scored as identical matches by
the sequence
alignment program ALIGN-2 in that programs alignment of A and B, and where Y
is the
total number of amino acid residues in B. It will be appreciated that where
the length of
amino acid sequence A is not equal to the length of amino acid sequence B, the
% amino acid
sequence identity of A to B will not equal the % amino acid sequence identity
of B to A.
Unless specifically stated otherwise, all % amino acid sequence identity
values used herein
are obtained as described in the immediately preceding paragraph using the
ALIGN-2
computer program.
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1001381 In some embodiments, the term "about" means within 10% of the stated
amount.
For instance, an antibody variable region comprising about 80% identity to a
reference
variable region may comprise 72% to 88% identity to the reference variable
region.
1001391
In certain aspects, antibodies are described herein that specifically bind
to TL1A
(Entrez Gene: 9966; UniProtKB: 095150). In some embodiments, the antibodies
specifically
bind to soluble TL1A. In some embodiments, the antibodies specifically bind to
membrane
bound TL1A. In some embodiments, an anti-TL1A antibody is provided having a
heavy
chain comprising four heavy chain framework regions (HCFR) and three heavy
chain
complementarity-determining regions (HCDR): HCFR1, HCDR1, HCFR2, HCDR2, HCFR3,
HCDR3, and HCFR4; and a light chain comprising four light chain framework
regions
(LCFR) and three light chain complementarity-determining regions (LCDR):
LCFR1,
LCDR1, LCFR2, LCDR2, LCFR3, LCDR3, and LCFR4. An anti-TL1A antibody may
comprise any region provided herein, for example, as provided in the tables,
the examples,
and the sequences.
1001401 Exemplary anti-TL1A CDRs
1001411 In certain embodiments, an anti-TL1A antibody comprises a HCDR1 as set
forth
by SEQ ID NO: 1. In certain embodiments, an anti-TL1A antibody comprises a
HCDR2 as
set forth by any one of SEQ ID NOS: 2-5. In certain embodiments, an anti-TL1A
antibody
comprises a HCDR3 as set forth by any one of SEQ ID NOS: 6-9. In certain
embodiments, an
anti-TL1A antibody comprises a LCDR1 as set forth by SEQ ID NO: 10. In certain
embodiments, an anti-TL1A antibody comprises a LCDR2 as set forth by SEQ ID
NO: 11. In
certain embodiments, an anti-TL1A antibody comprises a LCDR3 as set forth by
any one of
SEQ ID NOS: 12-15. In anon-limiting example, an anti-TL1A antibody comprises a
HCDR1
as set forth by SEQ ID NO: 1, a HCDR2 as set forth by SEQ ID NO: 2, a HCDR3 as
set forth
by SEQ ID NO: 6, a LCDR1 as set forth by SEQ ID NO: 10, a LCDR2 as set forth
by SEQ
ID NO: 11, and a LCDR3 as set forth by SEQ ID NO: 12.
1001421 In certain embodiments, an anti-TL1A antibody comprises a HCDRI,
HCDR2,
HCDR3, LCDR1, LCDR2, and LCDR3 selected from Table 6.
Table 6. Example CDR amino acid sequences
SEQ ID NO Description Sequence
1 HCDR1 GEDIQDTYMI-1
2 HCDR2 a RIDPASGHTKYDPKFQV
3 HCDR2b RIEPASGHIKYDPKFQG
4 HCDR2c RIDPASGHIKYDPKFQG
HCDR2d RIEPASGHIKYDPKFQV
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6 HCDR3 a SGGLPDV
7 HCDR3b ARSGGLPD V
8 HCDR3c SGGLPDW
9 HCDR3d ARSGGLPDW
LCDR1 RASSSVSYMY
11 LCDR2 ATSNLAS
12 LCDR3 a QQWEGNPRT
13 LCDR3b QQWKGNPRT
14 LCDR3c QQWSGNPRT
LCDR3d QQWSRNPRT
1001431 In certain embodiments, an anti-TL1A antibody comprises the CDRs set
forth in
antibody A, B, C, D, E, F, G, H, I, A2, B2, C2, D2, E2, F2, G2, H2, or I2 of
Table 10.
Table 10. CDR sequences from example anti-TL I A antibodies
Antibody Heavy Chain CDR SEQ ID NOS Light Chain CDR SEQ ID NOS
(CDR1, CDR2, CDR3) (CDR1, CDR2, CDR3)
A 1, 2, 6 10, 11, 12
1, 3, 8 10, 11, 12
1, 4, 8 10, 11, 12
1, 2, 6 10, 11, 13
1, 2, 6 10, 11, 14
1, 5, 8 10, 11, 12
1, 5, 8 10, 11, 13
1, 3, 8 10, 11, 13
A2 1, 2, 7 10, 11, 12
B2 1, 3, 9 10, 11, 12
C2 1, 4, 9 10, 11, 12
D2 1, 2, 7 10, 11, 13
E2 1, 2, 7 10, 11, 14
F2 1, 5, 9 10, 11, 12
G2 1, 5, 9 10, 11, 13
H2 1, 3, 9 10, 11, 13
1, 5, 8 10, 11, 15
12 1, 5, 9 10, 11, 15
1001441 In certain embodiments, an anti-TL1A antibody comprises the heavy
chain CDRs
set forth in an antibody selected from Table 7.
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Table 7. Example heavy chain variable region sequences
SEQ Description Sequence
ID
NO
101 217 VH, 158 VH QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVKQRPGQGL
EWMG RID PA S GHTKYDPKF QVRVTI TRDTS TS TVYME LS S LRS E DTA
VYYC A RSGGI ,P DVWGQGTTVTV S S
102 220 VH, 160 VH QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVKQRPGQGL
EWMGRID PA S GHTKYDPKF QVRVTMTRDTS TS TAYLE LS S LRS E DTA
VYYCARSGGLPDVWGQGTTVTVS S
103 223 VH, 200 EV QLVQ S GAEVKKPGA SVKV S CKA SGF DI
QDTYMIIWVRQRPGQGL
VH, 194 VL, 206 EWIGRIDPASGHTKYDPKFQVRATI I IDTSTSTAYLELSSLRSEDTAV
VH YY CARS GGLP DVWGQ GTTVTV S S
104 219 VH, 157 VH QVQLVQSGAEVKKPGA SVKVS CK
SGFDIQDTYIVIHWVKQRPGQGL
EWMGRID PA S GHTKYDPKF QVRVTI TRDTS TS TVYLE LS S LRS ED TAV
YY CARS GGLPDVWGQGTTVTV S S
105 221 VH, 125 VH QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVKQRPGQGL
EWMGRID PA S GHTKYDPKF QVRATI TRDTS TS TAYLE LS SLRSEDTAV
YY CARS GGLPDVWGQGTTVTV S S
106 213 VH, 162 VH QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQRPGQGL
EWMGRID P A SGHTKYDPKFQVRV'TT l'1D TS TS TVYME LS SLRS E DTA
VYYCARSGGLPDVWGQGTTVTVS S
107 212 VH, 100 QV QLV Q S GAEVKKP GA S VKV S
CKASGFDIQDTYMHWVRQRPGQGL
VH, 181 VH, 34 EWIGRIDPASGHTKYDPKFQVRATI I I DTSTSTAYLELS SLRSEDTAV
VH, 79 VH YY CARS GGLPDVWGQGTTVTV S S
108 107 VH, 211 QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVKQRPGQGL
VH, 15 VH, 30 EWIGRIDPASGHTKYDPKFQVRATITTDTSTSTAYLELSSLRSEDTAV
VH, 29 VH, 48 YYCARSGGLPDVWGQGTTVTVSS
VH, 49 VH, 50
VH. 51 VH, 52
VH, 56 VH
109 205 VH, 199 E V QLVQ SGAEVKKPGASVKV
SCKASGFDIQDTYMHWVKQRPGQGL
VH, 55 VH, 193 EWIGRIDPASGHTKYDPKFQVRATI I IDTSTSTAYLELSSLRSEDTAV
VH YY CARSGGLPDVWGQGTIVIVS S
110 129 VH, 139 QV QLV Q S GAEVKKP GA S VKV S
CKASGFDIQDTYMHWVRQRPGQGL
VH, 140 VH, EWMGRIDP A SGHTKYDPKFQVRV'TT l'1DTSTSTAYLELS
SLRSEDTAV
215 VH YY CARS GGLPDVWGQGTTVTV S S
111 214 VH, 128 QV QLV Q S GAEVKKP GA S VKV S
CKASGFDIQDTYMHWVRQRPGQGL
VH, 141 VH, EWMGRID PA S GHTKYDPKF QVRVTI TRDTS TS TAYLE LS
SLRSEDTAV
142 VH, 144 VH YYCARSGGLPDVWGQGTTVTVSS
112 216 VH, 123 VH QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQRPGQGL
EWIGRI DPA S GHTKYD PKF QVRVTI TRD TS TS TAYLE LS SLRS EDTAV
YYCARSGGLPDVWG QGTTVTVS S
113 122 VH QV QLV Q S GAEVKKP GA S VKV S
CKASGFDIQDTYMHWVRQRPGQGL
EWIGRI DPA S GHTKYD PKF QVRATI TRD TS TS TAYLE LS SLRS EDTAV
YY CARS GGLPDVWGQGTTVTV S S
114 222 VH, 126 VH QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVKQRPGQGL
EWMGRID PA S GHTKYDPKF QVRVTI TRDTS TS TAYLE LS SLRSEDTAV
YY CARSGGLPDVWGQGTTVTVS S
115 188 VH, 41 VH, QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVKQRPGQGL
102 VH EWIGRIDPASGHTKYDPKFQVRVTI I I DTS TS TAYLE LS
SLRSEDTAV
YYCARSGGLPDVWGQGTTVTVS S
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116 203 VH, 197 E V QLV Q S GAE VKKP GA S VKV S CKA SGF DI
QDTYMEIWVK QAP GQ GL
VH, 209 VH, EWMGRIEPAS GHI KYDPKFQ GRVTMTRD TS TS TW ME LS
SLRSEDTA
224 VH VYYCARSGGLPDWWGQGTTVTVS S
117 147 VH, 112 QV Q LV Q S GAE V KKP GA S VKV S CKA S GF D IQ
D TYMEIWVKQ RP G QGL
VH, 59 VH EWMGRIEPAS GHI KYDPKFQ GRVTWITRD TS TS TVY ME
LS SLRS E DTA
VYYCARSGGLPDWWGQGTINTVSS
118 127 VH QV Q LV Q S GAE V KKP GA S VKV S CKA S GF D IQ
D TYMEIWVKQ RP G QGL
EWMGRIDPA SGHTKYDPKF QVRVTI 1IDTSTSTAYLELS SLRSEDTAV
YY CARS GGLPDVWGQGTTVTV S S
119 159 VH, 218 VH QVQ LV Q S GAEVKKP GA S VKVS CKASGFDIQDTYM
HWVKQRPGQGL
EWMGRID PA SGHTKYDPKF QV RVTI TRD TS TS TAYMELS SLRSEDTA
VYYCA RS GGLP DVWGQ GTTVTV S S
120 103 VH, 45 VH, QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVKQRPGQGL
167 VH, 187 VH EWIGRIDPASGHTKYDPKFQVRVTITRDTSTSTAYLELSSLRSEDTAV
YY CARS GGLPDVWGQGTTVTV S S
121 64 VH, 148 VH, QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPGQGL
97 VH, 114 VH, EWMGRIEPASGHIKYDPKFQVRVTMTRDTSTSTVYMELSSLRSEDTA
130 VH, 133 VYYCARSGGLPDWWGQGTTVTVS S
VH, 137 VH,
155 VH
122 67 VH, 138 VH, QVQLVQSGAEVKKPGASVKVSCSGFDIQDTYMHWVRQAPGQGL
115 VH, 149 EWMGRIEPASGHIKYDPKFQVRATMTRDTSTSTVYMELSSLRSEDTA
VH, 134 VH, 98 VYYCARSGGLPDWWGQGTTVTVSS
VH, 156 VH
123 68 VH, 99 VH, QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPGQGL
116 VH EWMGRIEPA S GHI KY DPKFQV RVTI TRD TS TS
TVYMELS SLRSEDTAV
CARSGGLPDWWG QGTTVTVS S
124 94 VH, 113 VH, QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPGQGL
151 VH, 78 VH EWMGRIEPASGHIKYDPKFQVRATITRDTSTSTVYMELSSLRSEDTAV
YY CARS GGLPDWWGQGTTVTV S S
125 110 VH, 58 VH, QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVKQAPGQGL
136 VH, 146 EWMGRIEPAS GHI KYDPKFQ GRVTMTRD TS TS TW ME LS
SLRSEDTA
VH, 154 VH VYYCARSGGLPDWWGQGTTVTVSS
126 169 VH, 175 VH QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVKQAPGQGL
EWMGRID PA S GHIKYDP KF Q GRV TMTRD TS TS TVYMELS SLRSEDTA
VYYCARSGGLPDWWGQGTTVTVSS
127 173 VH, 179 VH QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVKQAPGQGL
EWMGRIEPASGHIKYDPKFQGRATMTRDTSTSTWMELSSLRSEDTA
VYYCARSGGLPDWWGQGTTVTVS S
128 96 VH, 132 VH, QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPGQGL
65 VH, 150 VH EWMGRIEPASGHIKYDPKFQGRATMTRDTSTSTVYMELS SLRSEDTA
VYYCARSGGLPDWWGQGTTVTVS S
129 196 VH, 202 E V QLV Q S GAE VKKP GA S VKV S CKA SGF DI QD
TYMEIWVRQAP GQGL
VH, 208 VH EWMGRIEP A SGHIKYDPKFQGRA TIVITRDTS TS TVYMELS
S LRSEDTA
VYYCARSGGLPDWWGQGTTVTVS S
130 172 VH, 178 VH QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPGQGL
EWMGRID PA S GHIKYDP KF Q GRA TMTRD TS TS TVYMELS SLRSEDTA
VYYCARSGGLPDWWGQGTTVTVS S
131 75 VI-I, 72 VI-L QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPGQGL
95 VH, 152 VH EWMGRIEPASGHIKYDPKFQGRATIFIDTSTSTVYMELSSLRSEDTAV
YY CA R S GGLP DWWGQ GTTVTV S S
132 174 VH, 180 VH QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPGQGL
EWMGRIEPASGHIKYDPKFQGRATMTRDTSTSTAYMELSSLRSEDTA
VYYCARSGGLPDWWGQGTTVTVS S
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133 109 VH, 91 VH, QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPGQGL
135 VH, 145 EWMGRIEPASGHIKYDPKFQGRVTMTRDTSTSTAYMELSSLRSEDTA
VH, 153 VH VYYCARSGGLPDWWGQGTTVTVS S
134 198 VH, 204 E V QLV Q S GAE VKKP GA S VKV S CKA SGF DI
QDTYME1WVRQAP GQ GL
VH, 210 VH EWMGRIEPAS GHIKYDPKFQ GRVTWITRD TS TS TAYME LS
SLRSEDTA
VYYCARSGGLPDWWGQGTTVTVS S
135 170 VH, 176 VH QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPGQGL
EWMGRI D PA S GHIKYDPKF Q GRV TMTRD TS TS TAYMELS S LRS E D TA
VYYCARSGGLPDWWGQGTTVTVS S
136 31 VH, 85 VH, QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPGQGL
86 VH, 87 VH, EWMGRIEPASGHIKYDPKFQGRVTMTRDTSTSTVYMELSSLRSEDTA
88 VH, 89 VH, VYYCARSGGLPDWWGQGTTVTVS S
90 VH, 143 VH
137 32 VH, 33 VH DVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPGQGL
EWMGRIEPAS GHIKYDPKFQ GRVTMTRD TS TS TVYME LS SLRSEDTA
VYYCARSGGLPDWWGQGTTVTVS S
138 35 VH, 182 VH QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMEIWVKQAPGQGL
EWIGRIDPASGHTKYDPKFQVRATII1DTSTSTAYLELSSLRSEDTAV
YYCARSGGLPDVWGQGTTVTVSS
139 36 VH, 81 VH, QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPGQGL
104 VH, 165 EWIGRIDPASGHTKYDPKFQVRATI
l'IDTSTSTAYLELSSLRSEDTAV
VH. YYCARSGGLPDVWGQGTTVTVSS
140 37 VH, 82 VH, QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVKQRPGQGL
101 VH, 183 VH EWMGRIDPASGHTKYDPKFQVRATIF1DTSTSTAYLELSSLRSEDTAV
YY CARS GGLPDVWGQGTTVTV S S
141 38 VH, 190 VH QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVKQRPGQGL
EWIGRIDPASGHTKYDPKFQVRATI l'IDTSTSTVYLELSSLRSEDTAV
YYCARSGGLPDVWGQGTTVTVSS
142 39 VH, 191 VH QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVKQRPGQGL
EW1GRIDPAS GHTKYDPKFQ VRATITTDTSTS TAYMELS S LRS E DTA V
YY CARS GGLPDVWGQGTTVTV S S
143 40 VH, 105 VH, QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVKQRPGQGL
192 VH
EWIGRIDPASGHTKYDPKFQVRAT1TTDTSTSTVYMELSSLRSEDTAV
YYCARSGGLPDVWGQGTTVTVSS
144 42 VH, 83 VH, QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVKQRPGQGL
186 VH EWIGRIDPASGHTKYDPKFQVRAT1V11.1DTS TS TAYLELS
SLRSEDTAV
YY CARSGGLPDVWGQGTTVTVS S
145 43 VH, 184 VH QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVKQRPGQGL
EWIGRIDPASGHTKYDPKFQVRATITRDTSTSTAYLELSSLRSEDTAV
YYCARSGGLPDVWGQGTTVTVSS
146 44 VH, 53 VH, QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVKQRPGQGL
166 VT-[ 189 VH EWIGRIDP A S CiHTKYDPKFQVRVTM l'IDTS TSTAYLELS S LRSEDTAV
YYCARSGGLPDVWGQGTTVTVSS
147 46 VH, 168 VH, QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVKQRPGQGL
185 VH
EWIGRIDPASGHTKYDPKFQVRAT1VITRDTSTSTAYLELSSLRSEDTAV
YYCARSGGLPDVWGQGTTVTVSS
148 47 VH QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVKQRPGQGL
EW1GRIDPASGHTKYDPKFQVRVTMTRDTSTSTAYLELS SLRSEDTAV
YYCARSGGLPDVWGQGTTVTVSS
149 54 VH DVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMEIWVKQRPGQGL
EWIGRIDPASGHTKYDPKFQVRATI l'IDTSTSTAYLELSSLRSEDTAV
YYCARSGGLPDVWGQGTTVTVSS
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150 57 VH, 111 VH QV Q LV Q S GAE VKKP GA S VKV S CKASGFDIQDTYM
HWVRQRPGQGL
EWMGRIEPAS GHI KYDPKFQ GRVTMTRD TS TS TW ME LS SLRSEDTA
VYYCARSGGLPDWWGQGTTVTVS S
151 60 VH, 117 VH QVQLVQ S GAEVKKP GAS VKVS CKASGFDIQDTYM
HWVRQAPGQGL
EWMGRID PA S GHIKYDP KF Q GRV TMTRDTS TS TVY ME L S SLRSEDTA
VYYCARSGGLPDWWGQGTTVTVS S
152 61 VH QV Q LV Q S GAE VKKP GA S VKV S CKASGFDIQDTYM
HWVRQAPGQGL
EWIGRI E PA S GHIKYDP KF Q GRV TMTRD TS TS TVYME L S SLRSEDTAV
YY CARS GGLP DWWGQGTTV TV S S
153 62 VH, 118 VH QVQLVQ S GAEVKKP GAS VKVS CKASGFDIQDTYM
HWVRQAPGQGL
EWIGRIDPAS GHI KYDPKFQ GRVTWITRDTS TS TVYME LS SLRSEDTAV
YY CARS GGLPDWWGQGTTVTV S S
154 63 VH, 120 VH QVQLVQ S GAEVKKP GA SVKVS CK A S GFDIQDTYMHWVRQ
A PGQGL
EW MG RIEPAS GHVKYDPKF QG RVTMTRDTS TSTVY MELS SLRS EDT
AVYYCARS GGLPDWWGQGTTVTVS S
155 66 VH QV Q LV Q S GAE VKKP GA S VKV S
CKASGFDIQDTYM,HVVVRQAPGQGL
EWMGRIEPAS GHI KYDPKFQ GRVTITRD TS TS TVYMELS SLRSEDTAV
YY CARS GGLPDWWGQGTTVTV S S
156 69 VH, 108 VH E V Q LV Q S GAE VKKP GA S VKV S CKA SGF DI
QDTYMEIWVRQAP GQ GL
EWMG RIEPAS GHI KYDPKFQG RVTMTRD TS TS TV \T ME LS SLRSEDTA
VYYCARSGG LP DWWG QGTTVTVS S
157 70 VH, 73 VH QVQLVQ S GAEVKKP GAS VKVS CKASGFDIQDTYM
HWVRQAPGQGL
EWMGRIEPASGHIKY DPKFQGRVIMITDTSTSTVYMELS SLRSEDTA
VYYCARSGGLPDWWGQGTTVTVS S
158 71 VH, 74 VH QV QLV Q S GAEVKKP GA S VKV S CKASGFDIQDTYM
HWVRQAPGQGL
EWMGRIEPAS GHI KYDPKFQ GRVTI 1. I DTS TS TVY ME LS SLRSEDTAV
YY CARSG G LP DWWG QGTTVTVS S
159 76 VH, 119 VH QVQLVQ S GAEVKKP GAS VKVS
CKASGFDIQDTYMIFIVVVRQAPGQGL
EWMGRIEPAS GHTKYDPKFQGRVTMTRDTS TS TVYMELS SLRSEDTA
VY Y CARS GGLPDWW GQGTTVTV S S
160 77 VH QV Q LV Q S GAE VKKP GA S VKV S CKASGFDIQDTYM
HWVRQAPGQGL
EWMGRIEPAS GHI KYDPKFQ GRATITRD TS TS TVYMELS SLRSEDTAV
YY CARSGGLPDWWGQGTTVTVS S
161 92 VH QV Q LV Q S GAE VKKP GA S VKV S CKASGFDIQDTYM
HWVRQAPGQGL
EWMGRIEP A S GHI KYDPKFQ GRVTMTRD TS TS MT LEL S SLRSEDTA
VYYCARSGGLPDWWGQGTTVTVS S
162 93 VH Q V QLV Q S GAE VKKP GAS VKVS CKASGFDIQDTYMHW
VRQAPGQGL
EWMGRIEPAS GHI KYDPKFQ GRVTMTRDTS TS TAYLEL S SLRSEDTA
VYYCARSGGLPDWWGQGTTVTVS S
163 121 VH QV Q LV Q S GAE VKKP GA S VKV S
CKASGFDIQDTYM,FIVVVRQRPGQGL
EWMGRIDPASGHTKYDPKFQVRATI 1IDTSTSTAYLELSSLRSEDTAV
YY CA RSGGLPDVWGQGTTVTVS S
164 124 VH QV Q LV Q S GAE VKKP GA S VKV S CKASGFDIQDTYM
HWVRQRPGQGL
EWIGRIDPASGHTKYDPKFQVRVTI I I DTS TS TAYLE LS SLRSEDTAV
YY CARS GGLPDVWGQGTTVTV S S
165 161 VH QV Q LV Q S GAE VKKP GA S VKV S
CKASGFDIQDTYMHVVVRQRPGQGL
EWMGRIDPASGHTKYDPKFQVRVTI 1IIJTSTSTVYLELS SLRSEDTAV
YY CARSGGLPDVWGQGTTVTVS S
166 163 VH QVQLVQ S AEVKKP A SVKVS CK A S
GFDIQDTYMHVVVRQRPG Q G L
EWMGRIDPASGHTKYDPKFQVRVTI 1IDTS TS TAYME LS SLRS EDTA
VYYCARSGGLPDVVVGQGTTVTVS S
167 164 VH QVQLVQ S GAEVKKP GAS VKVS CKASGFDIQDTYM
HWVRQRPGQGL
EWMGRID PA S GHTKYDPKF QVRV TM I _HOTS TS TAYLEL S SLRSEDTA
VYYCARSGGLPDVVVGQGTIVTVS S
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168 171 VH, 177 VH QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPGQGL
EWMGRIDPASGHIKYDPKFQGRATII1DTSTSTVYMELSSLRSEDTAV
YYCARSGGLPDWWGQGTTVTVSS
169 195 VH, 201 EVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPGQGL
VH, 207 VH
EWMGRIEPASGHIKYDPKFQGRATIFIDTSTSTVYMELSSLRSEDTAV
YYCARSGGLPDWWGQGTTVTVSS
1001451 In certain embodiments, an anti-TL1A antibody comprises the light
chain CDRs
set forth in an antibody selected from Table 8.
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Table 8. Example light chain variable region sequences
SEQ Description Sequence
ID
NO
201 217 VL, EIVLTQSPGILSLSPGERATLSCRASSSVSYMYWYQQ
219 VL, 221 VL, KPGQAPRPLIYATSNLA SGIPDRF SG SG
SGTDF'ILTIS
200 VIõ 213 VIõ RLEPEDFAVYYCQQWEGNPRTFGGGTKLEIK
212 VL, 211 VL,
199 VL, 214 VL,
216 VL, 222 VL,
203 VL, 147 VL,
218 VL, 179 VL,
148 VL, 149 VL,
151 VL, 180 VL, 175 VL,
178 VL, 145 VL, 146 VL,
150 VL, 152 VL, 176 VL,
177 VL, 201 VL, 202 VL,
204 VL, 215 VL, 224 VL
202 223 VL, 107 VL, EIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQ
205 VL, 181 VL, KPGQAPRLLIYATSNLASGIPDRFSGSGSGTDFTLTIS
188 VL, 64 VL, RLEPEDFAVYYCQQWEGNPRTFGGGTKLEIK
67 VL, 68 VL,
94 VL, 33 VL, 57 VL, 58
VL, 59 VL, 60 VL, 61 VL,
62 VL, 63 VL, 65 VL, 66
VL, 69 VL, 70 VL, 71 VL,
72 VL, 76 VL, 77 VL, 78
VL, 91 VL, 92 VL, 93 VL,
97 VL, 98 VL, 99 VL, 140
VL, 142 VL, 143 VL, 182
VL, 183 VL, 184 VL, 185
VL, 186 VL, 187 VL, 189
VL, 190 VL, 191 VL, 192
VL, 206 VL, 207 VL, 208
VL, 209 VL, 210 VL
203 15 VL EIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQ
KPGQAPRLLIYATSNLASGIPDRFSGSGSGTDFTLTIS
RLEPEDFAVYYCQQWSGNPRTFGGGTKLEIK
204 30 VL, 100 VL, EIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQ
129 VL, 122 VL, KPGQAPRLLIYATSNLASGIPDRFSGSGSGTDFTLTIS
127 VL, 126 VL, RLEPEDFAVYYCQQWKGNPRTFGGGTKLEIK
160 VL, 157 VL,
159 VL, 158 VL,
125 VL, 103 VL, 101 VL,
102 VL, 104 VL, 105 VL,
121 VL, 123 VL, 124 VL,
128 VL, 144 VL, 161 VL,
162 VL, 163 VL, 164 VL
205 110 VL, 197 VL, EIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQ
112 VL, 169 VL, KPGQAPRPWIYATSNLASGIPDRFSGSGSGTDFTLTIS
173 VL, 115 VL, RLEPEDFAVYYCQQWEGNPRTFGGGTKLEIK
113 VL, 96 VL,
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196 VL, 172 VL,
75 VL, 174 VL,
109 VL, 198 VL,
170 VL, 29 VL, 31 VL, 32
VL, 73 VL, 74 VL, 95 VL,
108 VL, 1 1 1 VL, 114 VL,
116 VL, 117 VL, 118 VL,
119 VL, 120 VL, 130 VL,
153 VL, 154 VL, 155 VL,
156 VL, 165 VL, 166 VL,
167 VL, 168 VL, 171 VL,
193 VL, 194 VL, 195 VL,
220 VL
206 134 VL, 132 VL, 133 VL, EIVLIQSPGILSLSPGERATLSCRASSSVSYMYWYQQ
135 VL, 136 VL KPGQAPRPLIYATSNLASGIPDRFSGSGSGTDFTLTIS
RLEPEDFAVYYCQQWKGNPRTFGGGTKLEIK
207 138 VL, 137 VL, 139 VL, EIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQ
141 VL KPGQAPRLLIYATSNLASGIPDRFSGSGSGTDFTLTIS
RLEPEDFAVYYCQQWSRNPRTFGGGTKLEIK
208 34 VL, 35 VL, 36 VL, 37 EIVLTQSPGTLSASPGERATMSCRASSSVSYMQ
VL, 38 VL, 39 VL, 40 VL, QKPGQAPRPWIYATSNLASGVPDRFSGSGSGTDYTL
41 VL, 42 VL, 43 VL, 44 TISRVEPEDFAVYYCQQWSGNPRTFGGGTKLEIK
VL, 45 VL, 46 VL, 47 VL,
53 VL, 54 VL, 55 VL, 79
VL, 81 VL, 82 VL, 83 VL
209 85 VL El VLTQ SPGTLSLSPGERATLS CRAS S S VS
YMYW YQQ
KPGQAPRLLIYATSNLASGVPDRFSGSGSGTDFTLTIS
RLEPEDFAVYYCQQWEGNPRTFGGGTKLEIK
210 48 VL EIVLTQ SPGTLSASPGERATLSCRA S S
SVSYMYWYQ
QKPGQAPRPWIYATSNLASGVPDRFSGSGSGTDYTL
TISRVEPEDFAVYYCQQWSGNPRTFGGGTKLEIK
211 49 VL EIVLTQSPGTLSASPGERATMSCRASSSVSYMQ
QKPGQAPRLLIYATSNLASGVPDRFSGSGSGTDYTLT
ISRVEPEDFAVYYCQQWSGNPRTFGGGTKLEIK
212 50 VL EIVLTQ SP GTLSAS PGERATMS CRA S S
SVSYMYWYQ
QKPGQAPRPWIYATSNLASGVPDRFSGSGSGTDFTLT
ISRVEPEDFAVYYCQQWSGNPRTFGGGTKLEIK
213 51 VL EIVLTQ SPGTLSASPGERATMSCRASS SVSYMYWYQ
QKPGQAPRPWIYATSNLASGVPDRFSGSGSGTDYTL
TISRLEPEDFAVYYCQQWSGNPRTFGGGTKLEIK
214 52 VL EIVLTQ SPGTLSASPGERATMS CRAS S S
VSY1\4)(AAWQ
QKPGQAPRPWIYATSNLASGVPDRFSGSGSGTDFTLT
ISRLEPEDFAVYYCQQWSGNPRTFGGGTKLEIK
215 56 VL EIVLTQSPGTLSASPGERATMSCRASSSVSYMWWQ
QKPGQAPRPWIYATSNLASGIPDRFSGSGSGTDYTLT
ISRVEPEDFAVYYCQQWSGNPRTFGGGTKLEIK
216 86 VL EIVLTQ SPGTLSLSPGERATLS CRAS S
SVSYMYWYQQ
KPGQAPRLLIYATSNLASGIPDRFSGSGSGTDYTLTIS
RLEPEDFAVYYCQQWEGNPRTFGGGTKLEIK
217 87 VL EIVLTQ SPGTLSLSPGERATLS CRAS S
SVSYMYWYQQ
KPGQAPRLLIYATSNLASGIPDRFSGSGSGTDFTLTIS
RVEPEDFAVYYCQQWEGNPRTFGGGTKLEIK
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218 88 VL EIVLTQ SPGTLSLSPGERATLS CRAS S
SVSYMYWYQQ
KPGQAPRLLIYATSNLASGIPDRF SG SGSGTDYTLTI S
RVE PE DFAVYY CQ QWE GNP RTF GGGTKLE IK
219 89 VL EIVLTQ SPGTLSASPGERATLSCRA S S
SVSYMYWYQ
QKPGQAPRLLIYATSNLAS GIPDRF S GS GS GTDF TLTI
S RLEPE DFAVYYCQ QWE GNP RTF GGGTKLE IK
220 90 VL EIVLTQ SPGTMSLSPGERATLS CRAS S
SVSYMYWYQ
QKPGQAPRLLIYATSNLAS GIPDRF S GS GS GTDF TLTI
SRLEPEDFAVYYCQ QWEGNPRTFGGGTKLEIK
1001461 In certain embodiments, an anti-TL1A antibody comprises the CDRs set
forth in
any one of the antibodies of Table!. For instance, an anti-TL1A antibody
comprises the
CDRs of antibody A15, A29, A30, A31, A32, A33, A34, A35, A36, A37, A38, A39,
A40,
A41, A42, A43, A44, A45, A46, A47, A48, A49, A50, A51, A52, A53, A54, A55,
A56, A57,
A58, A59, A60, A61, A62, A63, A64, A65, A66, A67, A68, A69, A70, A71, A72,
A73, A74,
A75, A76, A77, A78, A79, A81, A82, A83, A85, A86, A87, A88, A89, A90, A91,
A92, A93,
A94, A95, A96, A97, A98, A99, A100, A101, A102, A103, A104, A105, A107, A108,
A109,
A110, A111, A112, A113, A114,A115, A116, A117, A118, A119, A120,A121, A122,
A123, A124, A125, A126, A127, A128, A129, A130, A132, A133, A134, A135, A136,
A137, A138, A139, A140, A141,A142, A143, A144, A145, A146, A147, A148, A149,
A150, A151, A152, A153, A154, A155, A156, A157, A158, A159, A160, A161, A162,
A163, A164, A165, A166, Al 67, A168, A169, A170, Al 71, A172, Al 73, Al 74,
A175,
A176, A177, A178, A179, A180, A181, A182, A183, A184, A185, A186, A187, A188,
A189, A190, A191, A192, A193, A194, A195, A196, A197, A198, A199, A200, A201,
A202, A203, A204, A205, A206, A207, A208, A209, A210, A211, A212, A213, A214,
A215, A216, A217, A218, A219, A220, A221, A222, A223, A224, A500, or A501. In
anon-
limiting example, an anti-TL1A antibody comprises the CDRs of antibody A219.
1001471 Antibody CDRs may be defined by the Aho or Kab at, Chothia, or IMGT
methods.
1001481 Exemplary anti-TL1A Framework Regions
1001491 In certain embodiments, an anti-TLIA antibody comprises a heavy chain
(HC)
framework 1 (FRI) as set forth by SEQ ID NO: 304. In certain embodiments, an
anti-TL1A
antibody comprises a HC FR2 as set forth by any one of SEQ ID NOS: 305 or 313
. In certain
embodiments, an anti-TLIA antibody comprises a HC FR3 as set forth by any one
of SEQ ID
NOS: 306-307, 314-315. In certain embodiments, an anti-ILIA antibody comprises
a HC
FR4 as set forth by SEQ ID NO: 308. In certain embodiments, an anti-TLI A
antibody
comprises a LC FRI as set forth by SEQ ID NO: 309. In certain embodiments, an
anti-TLI A
antibody comprises a LC FR2 as set forth by SEQ ID NO: 310. In certain
embodiments, an
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anti-TL1A antibody comprises a LC FR3 as set forth by SEQ ID NO: 311. In
certain
embodiments, an anti-TL1A antibody comprises a LC FR4 as set forth by SEQ ID
NO: 312.
In a non-limiting example, an anti-TL1A antibody comprises a HC FR1 as set
forth by SEQ
ID NO: 304, a HC FR2 as set forth by SEQ ID NO: 305, a HC FR3 as set forth by
SEQ ID
NO: 306, a HC FR4 as set forth by SEQ ID NO: 308, a LC FR1 as set forth by SEQ
ID NO:
309, a LC FR2 as set forth by SEQ ID NO: 310, a LC FR3 as set forth by SEQ ID
NO: 311,
and a LC FR4 as set forth by SEQ ID NO: 312. In a non-limiting example, an
anti-TL1A
antibody comprises a HC FR1 as set forth by SEQ ID NO: 304, a HC FR2 as set
forth by
SEQ ID NO: 305, a HC FR3 as set forth by SEQ ID NO: 307, a HC FR4 as set forth
by SEQ
ID NO: 308, a LC FR1 as set forth by SEQ ID NO: 309, a LC FR2 as set forth by
SEQ ID
NO: 310, a LC FR3 as set forth by SEQ ID NO: 311, and a LC FR4 as set forth by
SEQ ID
NO: 312.
[00150] In certain embodiments, an anti-TL1A antibody comprises the heavy
chain
framework regions set forth in an antibody selected from Table 7. In certain
embodiments, an
anti-TL1A antibody comprises the light chain framework regions set forth in an
antibody
selected from Table 8. In certain embodiments, an anti-TL1A antibody comprises
the
framework regions set forth in any one of the antibodies of Table 1. For
instance, an anti-
TL1A antibody comprises the framework regions of antibody A15, A29, A30, A31,
A32,
A33, A34, A35, A36, A37, A38, A39, A40, A41, A42, A43, A44, A45, A46, A47,
A48, A49,
A50, A51, A52, A53, A54, A55, A56, A57, A58, A59, A60, A61, A62, A63, A64,
A65, A66,
A67, A68, A69, A70, A71, A72, A73, A74, A75, A76, A77, A78, A79, A81, A82,
A83, A85,
A86, A87, A88, A89, A90, A91, A92, A93, A94, A95, A96, A97, A98, A99, A100,
A101,
A102, A103, A104, A105, A107, A108, A109, A110, A111, A112, Al 13,A114, A115,
A116, A117, A118, A119, A120,A121, A122, A123, A124, A125, A126,A127, A128,
A129, A130, A132, A133, A134, A135, A136, A137, A138, A139, A140,A141, A142,
A143, A144, A145, A146, A147, A148, A149, A150, A151, A152, A153,A154, A155,
A156, A157, A158, A159, A160, A161, A162, A163, A164, A165, A166, A167, A168,
A169, A170, A171, A172, A173,A174, A175, A176, A177, A178, A179,A180, A181,
A182, A183, A184, A185, A186, A187, A188, A189, A190, A191, A192,A193, A194,
A195, A196, A197, A198, A199, A200, A201, A202, A203, A204, A205, A206, A207,
A208, A209, A210, A211, A212, A213, A214, A215, A216, A217, A218, A219, A220,
A221, A222, A223, A224, A500, or A501. In a non-limiting example, an anti-TL1A
antibody
comprises the framework region of antibody A219.
[00151] Antibody CDR and framework regions may be defined by the Aho or Kab
at,
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Chothia, or IMGT methods.
1001521 In some embodiments, an anti-TL1A antibody comprises a heavy chain
variable
framework region comprising a human IGHV1-46*02 framework or a modified human
IGHV1-46*02 framework, and a light chain variable framework region comprising
a human
IGKV3 -20 framework or a modified human IGKV3 -20 framework; wherein the heavy
chain
variable framework region and the light chain variable framework region
collectively
comprise no or fewer than nine amino acid modification(s) from the human IGHV1-
46*02
framework and the human IGKV3 -20 framework. In some embodiments, the amino
acid
modification(s) comprise: (a) a modification at amino acid position 45 in the
heavy chain
variable region; (b) a modification at amino acid position 47 in the heavy
chain variable
region; (c) a modification at amino acid position 55 in the heavy chain
variable region; (d) a
modification at amino acid position 78 in the heavy chain variable region; (e)
a modification
at amino acid position 80 in the heavy chain variable region; (f) a
modification at amino acid
position 82 in the heavy chain variable region; (g) a modification at amino
acid position 89 in
the heavy chain variable region; or (h) a modification at amino acid position
91 in the heavy
chain variable region, per Aho or Kabat numbering; or a combination of two or
more
modifications selected from (a) to (h). In some embodiments, the amino acid
modification(s)
comprise (a) R45K, (b) A47R, (c) M5 5I, (d) V78A, (e) M80I, (f) R82T, (g)
V89A, or (h)
M91L in the heavy chain variable region, per Aho or Kab at numbering; or a
combination of
two or more modifications selected from (a) to (h). In some embodiments, the
amino acid
modification(s) comprise: A47R. In some embodiments, the amino acid
modification(s)
comprise: A47R, M551, V78A, M801, R82T, V89A, and M91L; A47R, M801, and R82T;
A47R, M80I, R82T, V89A, and M9 1L; or A47R, M55I, V78A, M80I, V89A, and M9 IL.
In
some embodiments, the amino acid modification(s) comprise: R45K and A47R. In
some
embodiments, the amino acid modification(s) comprise: R45K, A47R, V89A, and
M91L. In
some embodiments, the amino acid modification(s) comprise: R45K and A47R, and
M80I. In
some embodiments, the amino acid modification(s) comprise: R45K, A47R, M80I,
and
M91L; R45K, A47R, V78A, M80I, V89A, and M9 IL; R45K, A47R, M551, V78A, M80I,
R82T, V89A, and M91L; R45K, A47R, M80I, V89A, and M91L; R45K, A47R, M.55I,
M80I,
R82T, V89A, and M91L; R45K, A47R, M80I, and V89A; R45K, A47R, M80I, R82T,
V89A,
M91L; or R45K, A47R, M551, M80I, V89A, and M91L. In some embodiments, the
amino
acid modification(s) comprise: R45K. In some embodiments, the amino acid
modification(s)
comprise: R45K and V78A. In some embodiments, the amino acid modification(s)
comprise:
V78A. In some embodiments, the amino acid modification(s) comprise: V78A and
V89A;
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V78A and M80I; or V78A, M80I, and R82T. In some embodiments, the amino acid
modification(s) comprise: V89A. In some embodiments, the amino acid
modification(s)
comprise: M80I. In some embodiments, the amino acid modification(s) comprises:
(a) a
modification at amino acid position 54 in the light chain variable region;
and/or (b) a
modification at amino acid position 55 in the light chain variable region, per
Aho or Kabat
numbering. In some embodiments, the amino acid modification(s) comprises L54P
in the
light chain variable region, per Aho or Kabat numbering. In some embodiments,
the amino
acid modification(s) comprises L5 5W in the light chain variable region, per
Aho or Kabat
numbering.
1001531 In some embodiments, an anti-TL1A antibody comprises a heavy chain
framework comprising SEQ ID NO: 301
(X1VOLVQSGAEVKKPGASVKVSCKAS[HCDR1]WVX2QX3PGQGLEWX4G[HCDR2]
RX5TX6TX7DTSTSTX8YX9ELSSLRSEDTAVYYCAR[HCDR3]WGQGTTVTVSS) or
SEQ ID NO: 302
(X1VOLVOSGAEVKKPGASVKVSCKAS[HCDR1]WVX2QX3PGQGLEWX4G[HCDR2]
RX5TX6TX7DTSTSTX8YX9ELSSLRSEDTAVYYC[HCDR3]WGQGTTVTVSS). In some
cases, XI is Q. In some cases, X1 =E. In some cases, X2 =R. In some cases, X2
=K. In
some cases, X3 = A. In some cases, X3 =R. In some cases, X4 = M. In some
cases, X4 = I.
In some cases, X5 =V. In some cases, X5 =A. In some cases, X6 =M. In some
cases, X6 =
I. In some cases, X7 =R. In some cases, X7 = T. In some cases, X8 = V. In some
cases, X8 =
A. In some cases, X9 =M. In some cases, X9 =L. In some embodiments, X1 is at
position 1
of IGHV1-46*02 as determined by Aho or Kabat numbering. In some embodiments,
X2 is at
position 45 of IGHVI -46*02 as determined by Aho or Kabat numbering. In some
embodiments, X3 is at position 47 of IGHV1 -46*02 as determined by Aho or
Kabat
numbering. In some embodiments, X4 is at position 55 of IGHVI -46*02 as
determined by
Aho or Kabat numbering. In some embodiments, X5 is at position 78 of IGHV1-
46*02 as
determined by Aho or Kabat numbering. In some embodiments, X6 is at position
80 of
IGHV1-46*02 as determined by Aho or Kabat numbering. In some embodiments, X7
is at
position 82 of IGHVI -46*02 as determined by Aho or Kabat numbering. In some
embodiments, X8 is at position 89 of IGHVI -46*02 as determined by Aho or
Kabat
numbering. In some embodiments, X9 is at position 91 of IGHVI -46*02 as
determined by
Aho or Kabat numbering.
1001541 In one aspect, provided herein is a first embodiment of an anti-TL1A
antibody
comprising a heavy chain framework comprising IGHV1-46*02, or a variant
thereof, wherein
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the variant comprises between about 1 and about 9 amino acid substitutions, or
between
about land about 20 amino acid substitutions, or about 1, 2, 3, 4, 5, 6, 7, 8,
9, 10, 11, 12, 13,
14, 15, 16, 17, 18, 19, or 20 amino acid substitutions from IGHV1-46*02
framework.
Additional embodiments include: (2) The anti-TL1A of embodiment (1), wherein
the heavy
chain framework comprises SEQ ID NO: 301. (3) The anti-TL1A of embodiment 2,
wherein
X1 = Q. (4) The anti-TL1A of embodiment 2, wherein X1 =E. (5) The anti-TL1A of
any one
of embodiments 2-4, wherein X2 =R. (6) The anti-TL1A of any one of embodiments
2-4,
wherein X2 =K. (7) The anti-TL1A of any one of embodiments 2-6, wherein X3 =A.
(8)
The anti-TL1A of any one of embodiments 2-6, wherein X3 =R. (9) The anti-ILIA
of any
one of embodiments 2-8, wherein X4 =M. (10) The anti-TL1A of any one of
embodiments
2-8, wherein X4 = I. (11) The anti-TL1A of any one of embodiments 2-10,
wherein X5 = V.
(12) The anti-TL1A of any one of embodiments 2-10, wherein X5 =A. (13) The
anti-TL1A
of any one of embodiments 2-12, wherein X6 =M. (14) The anti-TL1A of any one
of
embodiments 2-12, wherein X6 = I. (15) The anti-TL1A of any one of embodiments
2-14,
wherein X7 =R. (16) The anti-TL1A of any one of embodiments 2-14, wherein X7 =
T. (17)
The anti-TL1A of any one of embodiments 2-16, wherein X8 = V. (18) The anti-
TL1A of any
one of embodiments 2-16, wherein X8 = A. (19) The anti-TL1A of any one of
embodiments
2-18, wherein X9 =M. (20) The anti-TL1A of any one of embodiments 2-4, wherein
X9 =L.
(21) The anti-TL1A of any one of embodiments 1-20, comprising antibody A. (22)
The anti-
TL1A of any one of embodiments 1-20, comprising antibody B. (23) The anti-TL1A
of any
one of embodiments 1-20, comprising antibody C. (24) The anti-TL1A of any one
of
embodiments 1-20, comprising antibody D. (25) The anti-TL1A of any one of
embodiments
1-20, comprising antibody E. (26) The anti-TL1A of any one of embodiments 1-
20,
comprising antibody F. (27) The anti-TL1A of any one of embodiments 1-20,
comprising
antibody G or I. (28) The anti-TL1A of any one of embodiments 1-20, comprising
antibody
H. (34) The anti-TL1A of any one of embodiments 1-33, comprising a light chain
comprising a light chain framework comprising IGKV3-20*01, or a variant
thereof, wherein
the variant comprises between about 1 and about 2 substitutions, or between
about 1 and
about 20 amino acid substitutions, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
12, 13, 14, 15, 16,
17, 18, 19, or 20 amino acid substitutions in the framework. (35) The anti-
TL1A antibody of
embodiment 34, wherein X10 is L. (36) The anti-TL1A antibody of embodiment 34,
wherein
X10 is P. (37) The anti-TL1A antibody of any one of embodiments 34-36, wherein
X11 is L.
(38) The anti-TL1A antibody of any one of embodiments 34-36, wherein X11 is W.
[00155] In some embodiments, an anti-TL1A antibody comprises a light chain
framework
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comprising SEQ ID NO: 303
(EIVLTQSPGTLSLSPGERATLSC[LCDR1]WYQQKPGQAPRX10X11IY[LCDR2]GIPDR
FSGSGSGTDFTLTISRLEPEDFAVYYC[LCDR3]FGGGTKLEIK). In some cases, X10 is
L. In some cases, X10 is P. In some cases, X11 is L. In some cases, X11 is W.
In some
embodiments, X10 is at position 54 of IGKV3-20*01 as determined by Aho or
Kabat
numbering. In some embodiments, X11 is at position 55 of IGKV3-20*01 as
determined by
Aho or Kab at numbering.
[00156] In some embodiments, an anti-TL1A antibody comprises a heavy chain
framework comprising IGHV1-46*02. In some embodiments, an anti-TLI A antibody
comprises a heavy chain framework comprising a variant of IGHV1-46*02
comprising
between about 1 and about 20 amino acid substitutions from SEQ ID NO: 316. In
some
embodiments, an anti-TL1A antibody comprises a heavy chain framework
comprising a
variant of IGHV1-46*02 comprising between about 1 and about 9 amino acid
substitutions
from SEQ ID NO: 316. In some embodiments, an anti-TL1A antibody comprises a
heavy
chain framework comprising a variant of IGHV1-46*02 comprising about 1, 2, 3,
4, 5, 6, 7,
5,9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, or 20 amino acid substitutions
from SEQ ID NO:
316 in the framework. In some cases, the heavy chain framework substitution
comprises
Q1E, as determined by Aho or Kab at numbering. In some cases, the heavy chain
framework
substitution comprises R45K, as determined by Aho or Kabat numbering. In some
cases, the
heavy chain framework substitution comprises A47R, as determined by Aho or Kab
at
numbering. In some cases, the heavy chain framework substitution comprises
M55I, as
determined by Aho or Kab at numbering. In some cases, the heavy chain
framework
substitution comprises V78A, as determined by Aho or Kab at numbering. In some
cases, the
heavy chain framework substitution comprises M80I, as determined by Aho or
Kabat
numbering. In some cases, the heavy chain framework substitution comprises
R82T, as
determined by Aho or Kab at numbering. In some cases, the heavy chain
framework
substitution comprises V89A, as determined by Aho or Kab at numbering. In some
cases, the
heavy chain framework substitution comprises M91L, as determined by Aho or Kab
at
numbering.
1001571 In some embodiments, an anti-TL1A antibody comprises a light chain
framework
comprising IGKV3-20*01. In some embodiments, an anti-TL1A antibody comprises a
variant of IGKV3-20*01 comprising between about 1 and about 20 amino acid
substitutions
from SEQ ID NO: 317. In some embodiments, an anti-TL1A antibody comprises a
variant of
IGKV3-20*01 comprising about 1 amino acid substitution from SEQ ID NO: 317. In
some
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embodiments, an anti-TL1A antibody comprises a light chain framework
comprising a
variant of IGKV3-20*01 comprising about 2 amino acid substitutions from SEQ ID
NO: 317.
In some embodiments, an anti-TL1A antibody comprises a light chain framework
comprising
a variant of IGKV3-20*01 comprising about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11,
12,13, 14,15, 16,
17, 18, 19, or 20 amino acid substitutions from SEQ ID NO: 317 in the
framework. In some
cases, the light chain framework substitution comprises Q1E, as determined by
Aho or Kab at
numbering. In some cases, the light chain framework substitution comprises
R45K, as
determined by Aho or Kab at numbering.
1001581 In some embodiments, an anti-TL1A antibody comprises a heavy chain FRI
as set
forth by SEQ ID NO: 304. In some embodiments, an anti-TL1A antibody comprises
a heavy
chain FR2 as set forth by SEQ ID NO: 305. In some embodiments, an anti-TL1A
antibody
comprises a heavy chain FR2 as set forth by SEQ ID NO: 313. In some
embodiments, an
anti-TL1A antibody comprises a heavy chain FR3 as set forth by SEQ ID NO: 306.
In some
embodiments, an anti-TL1A antibody comprises a heavy chain FR3 as set forth by
SEQ ID
NO: 307. In some embodiments, an anti-TL1A antibody comprises a heavy chain
FR3 as set
forth by SEQ ID NO: 314. In some embodiments, an anti-TL1A antibody comprises
a heavy
chain FR3 as set forth by SEQ ID NO: 315. In some embodiments, an anti-TL1A
antibody
comprises a heavy chain FR4 as set forth by SEQ ID NO: 308. In some
embodiments, an
anti-TL1A antibody comprises a light chain FR1 as set forth by SEQ ID NO: 309.
In some
embodiments, an anti-TLIA antibody comprises alight chain FR2 as set forth by
SEQ ID
NO: 310. In some embodiments, an anti-TL1A antibody comprises a light chain
FR3 as set
forth by SEQ ID NO: 311. In some embodiments, an anti-TLIA antibody comprises
a light
chain FR4 as set forth by SEQ ID NO: 312.
1001591 In some embodiments, an anti-TL1A antibody comprises a framework
region of
Table 9A.
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Table 9A. Example framework sequences
SEQ Description Sequence
ID
NO
301 Variable Heavy 1 X1VQLVQSGAEVKKPGASVKVSCKAS [HCDR1 ]
WVX2QX3PGQG
LEWX4G [HCDR2 ] RX5TX6TX7DTSTSTX8YX9ELSSLRSEDTA
VYYCAR [HaDR3 ] INGQG'1"l'VIVSS
wherein each of X1 -X11 is independently selected from A, R, N,
D, C, Q, E, G, H, I, L, K, M, F, P, S, T, W, Y, or V
In some cases, X1 =Q or E
In some cases, X2 =R or K
In some cases, X3 = A or R
In some cases, X4 =M or I
In some cases, X5 = V or A
In some cases, X6 =M or I
In some cases, X7 =R or T
In some cases, X8 = V or A
In some cases, X9 =M or L
302 Variable Heavy 2 X1VQLVQSGAEVKKPGASVKVSCKAS [HCDR1 ]
WVX2QX3PGQG
LEWX4G [HCDR2 ] RX5TX6TX7DTSTSTX8YX9ELSSLRSEDTA
VYYC [HCDR3] WGQGTTVTVSS
wherein each of X1 -X11 is independently selected from A, R, N,
D, C, Q, E, G, H, I, L, K, M, F, P, S, T, W, Y, or V
In some cases, X1 = Q or E
In some cases, X2 =R or K
In some cases, X3 = A or R
In some cases, X4 =M or I
In some cases, X5 = V or A
In some cases, X6 =M or I
In some cases, X7 =R or T
In some cases, X8 = V or A
In some cases, X9 =M or L
303 Variable Light EIVLIQSPGILSLSPGERATLSC [LCDR1]
WYQQKPGQAPRX10
X11IY [ LCDR2 ] GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC
[ LCDR3] FGGGTKLEIK
wherein each of X10 and X11 is independently selected from A, R,
N, D, C, Q, E, G, H, I, L, K, M, F, P, S, T, W, Y, or V
In some cases, X10 =L or P
In some cases, XII =L or W
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304 219 HC FR1, QVQLVQSGAEVKKPGASVKVSCKAS
212 HC FR1
305 219 HC FR2 WVKQRPGQGLEWMG
306 219 HC FR3a RVTITRDTSTSTVYLELSSLRSEDTAVYYCAR
307 219 HC FR3b RVTITRDTSTSTVYLELSSLRSEDTAVYYC
308 219 HCFR4, WGQGTTVTVSS
212 HC FR4
309 219 LC FR1, EIVLTQSPGTLSLSPGERATLSC
212 LC FR1
310 219 LC FR2, WYQQKPGQAPRPLIY
212 LC FR2
311 219 LC FR3, GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC
212 LC FR3
312 219 LCFR4, FGGGTKLEIK
212 LC FR4
313 212 HC FR2 WVRQRPGQGLEWIG
314 212 HC FR3 a RATITTDTSTSTAYLELSSLRSEDTAVYYCAR
315 212 HC FR3b RATITTDTSTSTAYLELSSLRSEDTAVYYC
316 IGHV1-46*02 QVQLVQSGAEVKKPGASVKVSCKASGYTFNSYYMITAVVR
QAPGQGLEWMGIINPSGGSTSYAQKFQGRVTMTRDTSTST
VY1VIELSSLRSEDTAVYYCAR
317 IGKV3 -20 *01 EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPG
QAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFA
VYYCQQYGSSP
1001601 Exemplary anti-TL1A Variable Regions
1001611 In one aspect, provided herein is an anti-TL1A antibody comprising a
heavy chain
variable region comprising an amino acid sequence at least about 80%, 81%,
82%, 83%,
84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,
99%,
or 100% identical to any one of SEQ ID NOS: 101-169; and a light chain
variable region at
least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%,
92%,93%,
94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to any one of SEQ ID NOS: 201-
220.
1001621 Further provided herein is a first embodiment of an anti-IL1A antibody
comprising a heavy chain variable region and a light chain variable region Non-
limiting
additional embodiments include: (Embodiment 2) The anti-TL1A antibody of
embodiment 1,
wherein the heavy chain variable region comprises a sequence at least about
80%, 81%, 82%,
83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,
98%,
99%, or 100% identical to SEQ ID NO: 101 or a sequence having about 1, 2, 3,
4, 5, 6, 7, 8, 9
or 10 amino acid substitutions or deletions as compared to SEQ ID NO: 101.
(Embodiment 3)
The anti-IL1A antibody of embodiment 1, wherein the heavy chain variable
region
comprises a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%,
88%, 89%,
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90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID
NO:
102 or the heavy chain variable region comprises a sequence having about 1, 2,
3, 4, 5,6, 7,
8,9 or 10 amino acid substitutions or deletions as compared to SEQ ID NO: 102.
(Embodiment 4) The anti-TL1A antibody of embodiment 1, wherein the heavy chain
variable
region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%,
87%,
88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical
to
SEQ ID NO: 103 or the heavy chain variable region comprises a sequence having
about 1, 2,
3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared to
SEQ ID NO: 103.
(Embodiment 5) The anti-TL1A antibody of embodiment 1, wherein the heavy chain
variable
region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%,
87%,
88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical
to
SEQ ID NO: 104 or the heavy chain variable region comprises a sequence having
about 1,2,
3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared to
SEQ ID NO: 104
(Embodiment 6) The anti-TL1A antibody of embodiment 1, wherein the heavy chain
variable
region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%,
87%,
88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical
to
SEQ ID NO: 105 or the heavy chain variable region comprises a sequence having
about 1,2,
3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared to
SEQ ID NO: 105.
(Embodiment 7) The anti-TL1A antibody of embodiment 1, wherein the heavy chain
variable
region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%,
87%,
88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical
to
SEQ ID NO: 106 or the heavy chain variable region comprises a sequence having
about 1,2,
3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared to
SEQ ID NO: 106.
(Embodiment 8) The anti-TL1A antibody of embodiment 1, wherein the heavy chain
variable
region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%,
87%,
88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical
to
SEQ ID NO: 107 or the heavy chain variable region comprises a sequence having
about 1,2,
3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared to
SEQ ID NO: 107.
(Embodiment 9) The anti-TL1A antibody of embodiment 1, wherein the heavy chain
variable
region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%,
87%,
88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical
to
SEQ ID NO: 108 or the heavy chain variable region comprises a sequence having
about 1,2,
3,4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared to
SEQ ID NO: 108.
(Embodiment 10) The anti-TLIA antibody of embodiment 1, wherein the heavy
chain
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variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 109 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
109. (Embodiment 11) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 110 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
110. (Embodiment 12) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 111 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8,9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
111. (Embodiment 13) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 112 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
112. (Embodiment 14) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 113 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
113. (Embodiment 15) The anti-IL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 114 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
114. (Embodiment 16) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 115 or the heavy chain variable region comprises a sequence
having about 1,
2, 3,4, 5,6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
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115. (Embodiment 17) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 116 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
116. (Embodiment 18) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 117 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
117. (Embodiment 19) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 118 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
118. (Embodiment 20) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 119 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
119. (Embodiment 21) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 120 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compare
d to SEQ ID NO:
120. (Embodiment 22) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 121 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
121. (Embodiment 23) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 122 or the heavy chain variable region comprises a sequence
having about 1,
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2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
122. (Embodiment 24) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 123 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
123. (Embodiment 25) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 124 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
124. (Embodiment 26) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 125 or the heavy chain variable reon comprises a sequence having
about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
125. (Embodiment 27) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 126 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
126. (Embodiment 28) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 127 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
127. (Embodiment 29) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 128 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
128. (Embodiment 30) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
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to SEQ ID NO: 129 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
129. (Embodiment 31) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 130 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
130. (Embodiment 32) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 131 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
131. (Embodiment 33) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 132 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
132. (Embodiment 34) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 133 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
133. (Embodiment 35) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 134 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
134. (Embodiment 36) The anti-TL I A antibody of embodiment 1, wherein the
heavy chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 135 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
135. (Embodiment 37) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
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87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 136 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
136. (Embodiment 38) The anti-TLIA antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 137 or the heavy chain variable re0on comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
137. (Embodiment 39) The anti-TLIA antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 138 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
138. (Embodiment 40) The anti-TLIA antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 139 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
139. (Embodiment 41) The anti-TLIA antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 140 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
140. (Embodiment 42) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 141 or the heavy chain variable re0on comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
141. (Embodiment 43) The anti-TLIA antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 142 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
142. (Embodiment 44) The anti-TLIA antibody of embodiment 1, wherein the heavy
chain
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variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 143 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
143. (Embodiment 45) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 144 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
144. (Embodiment 46) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 145 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
145. (Embodiment 47) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 146 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
146. (Embodiment 48) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 147 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
147. (Embodiment 49) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 148 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
148. (Embodiment 50) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 149 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
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149. (Embodiment 51) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 150 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
150. (Embodiment 52) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 151 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
151. (Embodiment 53) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 152 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
152. (Embodiment 54) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 153 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
153. (Embodiment 55) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 154 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
154. (Embodiment 56) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 155 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
155. (Embodiment 57) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 156 or the heavy chain variable region comprises a sequence
having about 1,
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2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
156. (Embodiment 58) The anti-TLIA antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 157 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
157. (Embodiment 59) The anti-TLIA antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 158 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
158. (Embodiment 60) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 159 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
159. (Embodiment 61) The anti-TLIA antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 160 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
160. (Embodiment 62) The anti-TLIA antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 161 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
161. (Embodiment 63) The anti-TLIA antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 162 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
162. (Embodiment 64) The anti-TLIA antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
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to SEQ ID NO: 163 or the heavy chain variable re0on comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
163. (Embodiment 65) The anti-TLIA antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 164 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
164. (Embodiment 66) The anti-TLIA antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 165 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
165. (Embodiment 67) The anti-TLIA antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 166 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
166. (Embodiment 68) The anti-TLIA antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 167 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
167. (Embodiment 69) The anti-TLIA antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 168 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
168. (Embodiment 70) The anti-TLIA antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 169 or the heavy chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
169.
[00163] (Embodiment 71) The anti-TL1A antibody of any one of embodiments 1-70,
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wherein the light chain variable region comprises a sequence at least about
80%, 81%, 82%,
83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,
98%,
99%, or 100% identical to SEQ ID NO: 201 or the light chain variable region
comprises a
sequence having about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions
or deletions as
compared to SEQ ID NO: 201. (Embodiment 72) The anti-TL1A antibody of any one
of
embodiments 1-70, wherein the light chain variable region comprises a sequence
at least
about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%,
94%,
95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 202 or the light
chain variable
region comprises a sequence having about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino
acid
substitutions or deletions as compared to SEQ ID NO: 202. (Embodiment 73) The
anti-TL1A
antibody of any one of embodiments 1-70, wherein the light chain variable
region comprises
a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%,
90%,
91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO:
203 or
the light chain variable region comprises a sequence having about 1, 2, 3, 4,
5, 6, 7, 8,9 or 10
amino acid substitutions or deletions as compared to SEQ ID NO: 203.
(Embodiment 74) The
anti-TL1A antibody of any one of embodiments 1-70, wherein the light chain
variable region
comprises a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%,
88%, 89%,
90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID
NO:
204 or the light chain variable region comprises a sequence having about 1, 2,
3, 4, 5, 6, 7, 8,
9 or 10 amino acid substitutions or deletions as compared to SEQ ID NO: 204.
(Embodiment
75) The anti-TL1A antibody of any one of embodiments 1-70, wherein the light
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 205 or the light chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
205. (Embodiment 76) The anti-TL1A antibody of any one of embodiments 1-70,
wherein
the light chain variable region comprises a sequence at least about 80%, 81%,
82%, 83%,
84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,
99%,
or 100% identical to SEQ ID NO: 206 or the light chain variable region
comprises a sequence
having about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or
deletions as compared to
SEQ ID NO: 206. (Embodiment 77) The anti-TL1A antibody of any one of
embodiments 1-
70, wherein the light chain variable region comprises a sequence at least
about 80%, 81%,
82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%,
97%,
98%, 99%, or 100% identical to SEQ ID NO: 207 or the light chain variable
region comprises
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a sequence having about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid
substitutions or deletions as
compared to SEQ ID NO: 207. (Embodiment 78) The anti-TLIA antibody of any one
of
embodiments 1-70, wherein the light chain variable region comprises a sequence
at least
about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%,
94%,
95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 208 or the light
chain variable
region comprises a sequence having about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino
acid
substitutions or deletions as compared to SEQ ID NO: 208. (Embodiment 79) The
anti-TL1A
antibody of any one of embodiments 1-70, wherein the light chain variable
region comprises
a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%,
90%,
91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO:
209 or
the light chain variable region comprises a sequence having about 1, 2, 3, 4,
5, 6, 7, 8, 9 or 10
amino acid substitutions or deletions as compared to SEQ ID NO: 209.
(Embodiment 80) The
anti-TLIA antibody of any one of embodiments 1-70, wherein the light chain
variable region
comprises a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%,
88%, 89%,
90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID
NO:
210 or the light chain variable region comprises a sequence having about 1, 2,
3, 4, 5, 6, 7, 8,
9 or 10 amino acid substitutions or deletions as compared to SEQ ID NO: 210.
(Embodiment
81) The anti-TLIA antibody of any one of embodiments 1-70, wherein the light
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 211 or the light chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
211. (Embodiment 82) The anti-TL1A antibody of any one of embodiments 1-70,
wherein
the light chain variable region comprises a sequence at least about 80%, 81%,
82%, 83%,
84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,
99%,
or 100% identical to SEQ ID NO: 212 or the light chain variable region
comprises a sequence
having about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or
deletions as compared to
SEQ ID NO: 212. (Embodiment 83) The anti-TL1A antibody of any one of
embodiments 1-
70, wherein the light chain variable region comprises a sequence at least
about 80%, 81%,
82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%,
97%,
98%, 99%, or 100% identical to SEQ ID NO: 213 or the light chain variable
region comprises
a sequence having about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid
substitutions or deletions as
compared to SEQ ID NO: 213. (Embodiment 84) The anti-TL1A antibody of any one
of
embodiments 1-70, wherein the light chain variable region comprises a sequence
at least
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about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%,
94%,
95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 214 or the light
chain variable
region comprises a sequence having about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino
acid
substitutions or deletions as compared to SEQ ID NO: 214. (Embodiment 85) The
anti-TL1A
antibody of any one of embodiments 1-70, wherein the light chain variable
region comprises
a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%,
90%,
91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO:
215 or
the light chain variable region comprises a sequence having about 1, 2, 3, 4,
5,6, 7, 8,9 or 10
amino acid substitutions or deletions as compared to SEQ ID NO: 215.
(Embodiment 86) The
anti-TL1A antibody of any one of embodiments 1-70, wherein the light chain
variable region
comprises a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%,
88%, 89%,
90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID
NO:
216 or the light chain variable region comprises a sequence having about 1, 2,
3, 4, 5, 6, 7, 8,
9 or 10 amino acid substitutions or deletions as compared to SEQ ID NO: 216.
(Embodiment
87) The anti-TL1A antibody of any one of embodiments 1-70, wherein the light
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 217 or the light chain variable region comprises a sequence
having about 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared
to SEQ ID NO:
217. (Embodiment 88) The anti-TL1A antibody of any one of embodiments 1-70,
wherein
the light chain variable region comprises a sequence at least about 80%, 81%,
82%, 83%,
84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,
99%,
or 100% identical to SEQ ID NO: 218 or the light chain variable region
comprises a sequence
having about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or
deletions as compared to
SEQ ID NO: 218. (Embodiment 89) The anti-TL1A antibody of any one of
embodiments 1-
70, wherein the light chain variable region comprises a sequence at least
about 80%, 81%,
82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%,
97%,
98%, 99%, or 100% identical to SEQ ID NO: 219 or the light chain variable
region comprises
a sequence having about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid
substitutions or deletions as
compared to SEQ ID NO: 219. (Embodiment 90) The anti-TL1A antibody of any one
of
embodiments 1-70, wherein the light chain variable region comprises a sequence
at least
about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%,
94%,
95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 220 or the light
chain variable
region comprises a sequence having about 1, 2, 3, 4, 5, 6, 7, 8,9 or 10 amino
acid
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substitutions or deletions as compared to SEQ ID NO: 220.
1001641 (Embodiment 91) The anti-TL1A antibody of embodiment 1, wherein the
heavy
chain variable region comprises a sequence at least about 80%, 81%, 82%, 83%,
84%, 85%,
86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical to SEQ ID NO: 101, and the light chain variable region comprises a
sequence at
least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%,
92%,93%,
94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 201. (Embodiment
92)
The anti-TL1A antibody of embodiment 1, wherein the heavy chain variable
region
comprises a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%,
88%, 89%,
90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID
NO:
102, and the light chain variable region comprises a sequence at least about
80%, 81%, 82%,
83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,
98%,
99%, or 100% identical to SEQ ID NO: 205. (Embodiment 93) The anti-TL1A
antibody of
embodiment 1, wherein the heavy chain variable region comprises a sequence at
least about
80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,
95%,
96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 103, and the light chain
variable
region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%,
87%,
88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical
to
SEQ ID NO: 202. (Embodiment 94) The anti-TL1A antibody of embodiment 1,
wherein the
heavy chain variable region comprises a sequence at least about 80%, 81%, 82%,
83%, 84%,
85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or
100% identical to SEQ ID NO: 104, and the light chain variable region
comprises a sequence
at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%,
92%,
93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 201.
(Embodiment 95) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 105, and the light chain variable region comprises a sequence at
least about
80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,
95%,
96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 201.
1001651 (Embodiment 96) The anti-TL1A antibody of embodiment 1,
wherein the heavy
chain variable region comprises a sequence at least about 80%, 81%, 82%, 83%,
84%, 85%,
86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical to SEQ ID NO: 103, and the light chain variable region comprises a
sequence at
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least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%,
92%,93%,
94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 201. (Embodiment
97)
The anti-TL1A antibody of embodiment 1, wherein the heavy chain variable
region
comprises a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%,
88%, 89%,
90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID
NO:
106, and the light chain variable region comprises a sequence at least about
80%, 81%, 82%,
83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,
98%,
99%, or 100% identical to SEQ ID NO: 201. (Embodiment 98) The anti-TL1A
antibody of
embodiment 1, wherein the heavy chain variable region comprises a sequence at
least about
80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,
95%,
96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 107, and the light chain
variable
region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%,
87%,
88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical
to
SEQ ID NO: 202. (Embodiment 99) The anti-TL1A antibody of embodiment 1,
wherein the
heavy chain variable region comprises a sequence at least about 80%, 81%, 82%,
83%, 84%,
85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or
100% identical to SEQ ID NO: 108, and the light chain variable region
comprises a sequence
at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%,
92%,
93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 202.
(Embodiment 100) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 109, and the light chain variable region comprises a sequence at
least about
80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,
95%,
96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 202.
1001661 (Embodiment 101) The anti-TL1A antibody of embodiment 1,
wherein the heavy
chain variable region comprises a sequence at least about 80%, 81%, 82%, 83%,
84%, 85%,
86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical to SEQ ID NO: 108, and the light chain variable region comprises a
sequence at
least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%,
92%,93%,
94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 201. (Embodiment
102)
The anti-TL1A antibody of embodiment 1, wherein the heavy chain variable
region
comprises a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%,
88%, 89%,
90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID
NO:
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109, and the light chain variable region comprises a sequence at least about
80%, 81%, 82%,
83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,
98%,
99%, or 100% identical to SEQ ID NO: 201. (Embodiment 103) The anti-TL1A
antibody of
embodiment 1, wherein the heavy chain variable region comprises a sequence at
least about
80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,
95%,
96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 108, and the light chain
variable
region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%,
87%,
88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical
to
SEQ ID NO: 203. (Embodiment 104) The anti-TL1A antibody of embodiment 1,
wherein the
heavy chain variable region comprises a sequence at least about 80%, 81%, 82%,
83%, 84%,
85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or
100% identical to SEQ ID NO: 108, and the light chain variable region
comprises a sequence
at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%,
92%,
93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 204.
(Embodiment 105) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 107, and the light chain variable region comprises a sequence at
least about
80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,
95%,
96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 204.
1001671 (Embodiment 106) The anti-TL1A antibody of embodiment 1,
wherein the heavy
chain variable region comprises a sequence at least about 80%, 81%, 82%, 83%,
84%, 85%,
86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical to SEQ ID NO: 107, and the light chain variable region comprises a
sequence at
least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%,
92%,93%,
94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 202. (Embodiment
107)
The anti-TL1A antibody of embodiment 1, wherein the heavy chain variable
region
comprises a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%,
88%, 89%,
90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID
NO:
110, and the light chain variable region comprises a sequence at least about
80%, 81%, 82%,
83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,
98%,
99%, or 100% identical to SEQ ID NO: 204. (Embodiment 108) The anti-TL1A
antibody of
embodiment 1, wherein the heavy chain variable region comprises a sequence at
least about
80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,
95%,
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96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 111, and the light chain
variable
region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%,
87%,
88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical
to
SEQ ID NO: 201. (Embodiment 109) The anti-TL1A antibody of embodiment 1,
wherein the
heavy chain variable region comprises a sequence at least about 80%, 81%, 82%,
83%, 84%,
85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or
100% identical to SEQ ID NO: 112, and the light chain variable region
comprises a sequence
at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%,
92%,
93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 201.
(Embodiment 110) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 113, and the light chain variable region comprises a sequence at
least about
80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,
95%,
96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 204.
1001681 (Embodiment 111) The anti-TL1A antibody of embodiment 1, wherein the
heavy
chain variable region comprises a sequence at least about 80%, 81%, 82%, 83%,
84%, 85%,
86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical to SEQ ID NO: 114, and the light chain variable region comprises a
sequence at
least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%,
92%,93%,
94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 201. (Embodiment
112)
The anti-TL1A antibody of embodiment 1, wherein the heavy chain variable
region
comprises a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%,
88%, 89%,
90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID
NO:
115, and the light chain variable region comprises a sequence at least about
80%, 81%, 82%,
83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,
98%,
99%, or 100% identical to SEQ ID NO: 202. (Embodiment 113) The anti-TL1A
antibody of
embodiment 1, wherein the heavy chain variable region comprises a sequence at
least about
80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,
95%,
96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 116, and the light chain
variable
region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%,
87%,
88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical
to
SEQ ID NO: 201. (Embodiment 114) The anti-TL1A antibody of embodiment 1,
wherein the
heavy chain variable region comprises a sequence at least about 80%, 81%, 82%,
83%, 84%,
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85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or
100% identical to SEQ ID NO: 117, and the light chain variable region
comprises a sequence
at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%,
92%,
93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 201.
(Embodiment 115) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 118, and the light chain variable region comprises a sequence at
least about
80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,
95%,
96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 204.
1001691 (Embodiment 116) The anti-TL1A antibody of embodiment 1,
wherein the heavy
chain variable region comprises a sequence at least about 80%, 81%, 82%, 83%,
84%, 85%,
86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical to SEQ ID NO: 114, and the light chain variable region comprises a
sequence at
least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%,
92%,93%,
94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 204. (Embodiment
117)
The anti-TL1A antibody of embodiment 1, wherein the heavy chain variable
region
comprises a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%,
88%, 89%,
90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID
NO:
102, and the light chain variable region comprises a sequence at least about
80%, 81%, 82%,
83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,
98%,
99%, or 100% identical to SEQ ID NO: 204. (Embodiment 118) The anti-TL1A
antibody of
embodiment 1, wherein the heavy chain variable region comprises a sequence at
least about
80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,
95%,
96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 104, and the light chain
variable
region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%,
87%,
88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical
to
SEQ ID NO: 204. (Embodiment 119) The anti-TL1A antibody of embodiment 1,
wherein the
heavy chain variable region comprises a sequence at least about 80%, 81%, 82%,
83%, 84%,
85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or
100% identical to SEQ ID NO: 119, and the light chain variable region
comprises a sequence
at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%,
92%,
93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 204.
(Embodiment 120) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
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variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 119, and the light chain variable region comprises a sequence at
least about
80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,
95%,
96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 201.
1001701 (Embodiment 121) The anti-TL1A antibody of embodiment 1,
wherein the heavy
chain variable region comprises a sequence at least about 80%, 81%, 82%, 83%,
84%, 85%,
86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical to SEQ ID NO: 101, and the light chain variable region comprises a
sequence at
least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%,
92%,93%,
94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 204. (Embodiment
122)
The anti-TL1A antibody of embodiment 1, wherein the heavy chain variable
region
comprises a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%,
88%, 89%,
90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID
NO:
105, and the light chain variable region comprises a sequence at least about
80%, 81%, 82%,
83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,
98%,
99%, or 100% identical to SEQ ID NO: 204. (Embodiment 123) The anti-TL1A
antibody of
embodiment 1, wherein the heavy chain variable region comprises a sequence at
least about
80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,
95%,
96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 120, and the light chain
variable
region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%,
87%,
88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical
to
SEQ ID NO: 204. (Embodiment 124) The anti-TL1A antibody of embodiment 1,
wherein the
heavy chain variable region comprises a sequence at least about 80%, 81%, 82%,
83%, 84%,
85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or
100% identical to SEQ ID NO: 121, and the light chain variable region
comprises a sequence
at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%,
92%,
93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 202.
(Embodiment 125) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 122, and the light chain variable region comprises a sequence at
least about
80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,
95%,
96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 202.
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1001711 (Embodiment 126) The anti-TL1A antibody of embodiment 1,
wherein the heavy
chain variable region comprises a sequence at least about 80%, 81%, 82%, 83%,
84%, 85%,
86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical to SEQ ID NO: 122, and the light chain variable region comprises a
sequence at
least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%,
92%,93%,
94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 207. (Embodiment
127)
The anti-TL1A antibody of embodiment 1, wherein the heavy chain variable
region
comprises a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%,
88%, 89%,
90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID
NO:
123, and the light chain variable region comprises a sequence at least about
80%, 81%, 82%,
83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,
98%,
99%, or 100% identical to SEQ ID NO: 202. (Embodiment 128) The anti-TL1A
antibody of
embodiment 1, wherein the heavy chain variable region comprises a sequence at
least about
80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,
95%,
96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 124, and the light chain
variable
region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%,
87%,
88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical
to
SEQ ID NO: 202. (Embodiment 129) The anti-TL1A antibody of embodiment 1,
wherein the
heavy chain variable region comprises a sequence at least about 80%, 81%, 82%,
83%, 84%,
85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or
100% identical to SEQ ID NO: 125, and the light chain variable region
comprises a sequence
at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%,
92%,
93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 205.
(Embodiment 130) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 116, and the light chain variable region comprises a sequence at
least about
80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,
95%,
96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 205.
1001721 (Embodiment 131) The anti-TL1A antibody of embodiment 1,
wherein the heavy
chain variable region comprises a sequence at least about 80%, 81%, 82%, 83%,
84%, 85%,
86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical to SEQ ID NO: 117, and the light chain variable region comprises a
sequence at
least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%,
92%,93%,
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94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 205. (Embodiment
132)
The anti-TLIA antibody of embodiment 1, wherein the heavy chain variable
region
comprises a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%,
88%, 89%,
90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID
NO:
126, and the light chain variable region comprises a sequence at least about
80%, 81%, 82%,
83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,
98%,
99%, or 100% identical to SEQ ID NO: 205. (Embodiment 133) The anti-TL1A
antibody of
embodiment 1, wherein the heavy chain variable region comprises a sequence at
least about
80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,
95%,
96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 127, and the light chain
variable
region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%,
87%,
88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical
to
SEQ ID NO: 205. (Embodiment 134) The anti-TLIA antibody of embodiment 1,
wherein the
heavy chain variable region comprises a sequence at least about 80%, 81%, 82%,
83%, 84%,
85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or
100% identical to SEQ ID NO: 127, and the light chain variable region
comprises a sequence
at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%,
92%,
93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 201.
(Embodiment 135) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 121, and the light chain variable region comprises a sequence at
least about
80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,
95%,
96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 201.
[00173] (Embodiment 136) The anti-TLIA antibody of embodiment 1,
wherein the heavy
chain variable region comprises a sequence at least about 80%, 81%, 82%, 83%,
84%, 85%,
86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical to SEQ ID NO: 122, and the light chain variable region comprises a
sequence at
least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%,
92%,93%,
94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 205. (Embodiment
137)
The anti-TLIA antibody of embodiment 1, wherein the heavy chain variable
region
comprises a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%,
88%, 89%,
90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID
NO:
122, and the light chain variable region comprises a sequence at least about
80%, 81%, 82%,
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83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,
98%,
99%, or 100% identical to SEQ ID NO: 201. (Embodiment 138) The anti-TL1A
antibody of
embodiment 1, wherein the heavy chain variable region comprises a sequence at
least about
80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,
95%,
96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 122, and the light chain
variable
region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%,
87%,
88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical
to
SEQ ID NO: 206. (Embodiment 139) The anti-TL1A antibody of embodiment 1,
wherein the
heavy chain variable region comprises a sequence at least about 80%, 81%, 82%,
83%, 84%,
85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or
100% identical to SEQ ID NO: 124, and the light chain variable region
comprises a sequence
at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%,
92%,
93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 205.
(Embodiment 140) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 124, and the light chain variable region comprises a sequence at
least about
80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,
95%,
96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 201.
[00174] (Embodiment 141) The anti-TL1A antibody of embodiment 1,
wherein the heavy
chain variable region comprises a sequence at least about 80%, 81%, 82%, 83%,
84%, 85%,
86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical to SEQ ID NO: 128, and the light chain variable region comprises a
sequence at
least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%,
92%,93%,
94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 205. (Embodiment
142)
The anti-TL1A antibody of embodiment 1, wherein the heavy chain variable
region
comprises a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%,
88%, 89%,
90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID
NO:
128, and the light chain variable region comprises a sequence at least about
80%, 81%, 82%,
83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,
98%,
99%, or 100% identical to SEQ ID NO: 206. (Embodiment 143) The anti-TL1A
antibody of
embodiment 1, wherein the heavy chain variable region comprises a sequence at
least about
80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,
95%,
96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 129, and the light chain
variable
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region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%,
87%,
88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical
to
SEQ ID NO: 205. (Embodiment 144) The anti-TL1A antibody of embodiment 1,
wherein the
heavy chain variable region comprises a sequence at least about 80%, 81%, 82%,
83%, 84%,
85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or
100% identical to SEQ ID NO: 130, and the light chain variable region
comprises a sequence
at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%,
92%,
93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 205.
(Embodiment 145) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 131, and the light chain variable region comprises a sequence at
least about
80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,
95%,
96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 205.
1001751 (Embodiment 146) The anti-TL1A antibody of embodiment 1,
wherein the heavy
chain variable region comprises a sequence at least about 80%, 81%, 82%, 83%,
84%, 85%,
86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical to SEQ ID NO: 132, and the light chain variable region comprises a
sequence at
least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%,
92%,93%,
94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 205. (Embodiment
147)
The anti-TL1A antibody of embodiment 1, wherein the heavy chain variable
region
comprises a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%,
88%, 89%,
90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID
NO:
133, and the light chain variable region comprises a sequence at least about
80%, 81%, 82%,
83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,
98%,
99%, or 100% identical to SEQ ID NO: 205. (Embodiment 148) The anti-TL1A
antibody of
embodiment 1, wherein the heavy chain variable region comprises a sequence at
least about
80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,
95%,
96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 134, and the light chain
variable
region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%,
87%,
88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical
to
SEQ ID NO: 205. (Embodiment 149) The anti-TL1A antibody of embodiment 1,
wherein the
heavy chain variable region comprises a sequence at least about 80%, 81%, 82%,
83%, 84%,
85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or
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100% identical to SEQ ID NO: 135, and the light chain variable region
comprises a sequence
at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%,
92%,
93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 205.
(Embodiment 150) The anti-TL1A antibody of embodiment 1, wherein the heavy
chain
variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%,
85%, 86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to SEQ ID NO: 126, and the light chain variable region comprises a sequence at
least about
80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,
95%,
96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 201. (Embodiment 151) The
anti-
TL1A antibody of embodiment 1, wherein the heavy chain variable region
comprises a
sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%,
91%,
92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 130,
and the
light chain variable region comprises a sequence at least about 80%, 81%, 82%,
83%, 84%,
85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or
100% identical to SEQ ID NO: 201. (Embodiment 152) The anti-TL1A antibody of
embodiment 1, wherein the heavy chain variable region comprises a sequence at
least about
80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,
95%,
96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 132, and the light chain
variable
region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%,
87%,
88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical
to
SEQ ID NO: 201. (Embodiment 153) The anti-TL1A antibody of embodiment 1,
comprising
A500. (Embodiment 154) The anti-TL1A antibody of embodiment 1, comprising
A501.
1001761 Exemplary anti-TL1A Constant Regions
1001771 In some embodiments, one or more amino acid modifications may be
introduced
into the Fragment crystallizable (Fc) region of a human or humanized antibody,
thereby
generating an Fc region variant. An Fc region may comprise a C-terminal region
of an
immunoglobulin heavy chain that comprises a hinge region, CH2 domain, CH3
domain, or
any combination thereof. As used herein, an Fc region includes native sequence
Fc regions
and variant Fc regions. The Fc region variant may comprise a human Fc region
sequence
(e.g., a human IgGl, IgG2, IgG3 or IgG4 Fc region) comprising an amino acid
modification
(e.g., a substitution, addition, or deletion) at one or more amino acid
positions. In an
exemplary embodiment, the Fc region comprises any one of SEQ ID NOS: 320-367
In some
embodiments, the anti-TL1A antibody comprises a constant region comprising any
one of
SEQ ID NOS: 319, 368-381.
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1001781 In some embodiments, antibodies of this disclosure have a reduced
effector
function as compared to a human IgG. Effector function refers to a biological
event resulting
from the interaction of an antibody Fc region with an Fc receptor or ligand.
Non-limiting
effector functions include Clq binding, complement dependent cytotoxicity
(CDC), Fc
receptor binding, antibody-dependent cell-mediated cytotoxicity (ADCC),
antibody -
dependent cellular phagocytosis (ADCP), cytokine secretion, immune complex-
mediated
antigen uptake by antigen presenting cells, down regulation of cell surface
receptors (e.g., B
cell receptor), and B cell activation. In some cases, antibody-dependent cell-
mediated
cytotoxicity (ADCC) refers to a cell-mediated reaction in which nonspecific
cytotoxic cells
expressing Fc receptors (e.g., natural killer cells, neutrophils, macrophages)
recognize bound
antibody on a target cell, subsequently causing lysis of the target cell. In
some cases,
complement dependent cytotoxicity (CDC) refers to ly sing of a target cells in
the presence of
complement, where the complement action pathway is initiated by the binding of
Clq to
antibody bound with the target.
1001791 Some Fc regions have a natural lack of effector function, and some Fc
regions can
comprise mutations that reduce effector functions For instance, IgG4 has low
ADCC and
CDC activities and IgG2 has low ADCC activity.
1001801 The disclosure provides antibodies comprising Fc regions characterized
by
exhibiting ADCC that is reduced by at least about 30%, at least about 40%, at
least about
50%, at least about 60%, at least about 70% or more as compared to an antibody
comprising
a non-variant Fc region, i.e., an antibody with the same sequence identity but
for the
sub stitution(s) that decrease ADCC (such as human IgGl, SEQ ID NO: 320). The
disclosure
provides antibodies comprising Fc regions characterized by exhibiting CDC that
is reduced
by at least about 30%, at least about 40%, at least about 50%, at least about
60%, at least
about 70% or more as compared to an antibody comprising a non-variant Fc
region, i.e., an
antibody with the same sequence identity but for the sub stitution(s) that
decrease CDC (such
as human IgGl, SEQ ID NO: 320). In certain embodiments, the antibodies of this
disclosure
have reduced effector function as compared with human IgG1 . In certain
embodiments,
antibodies herein have no detectable ADCC activity. In certain embodiments,
the reduction
and/or abatement of ADCC activity may be attributed to the reduced affinity
antibodies of the
invention exhibit for Fc ligands and/or receptors. In certain embodiments,
antibodies herein
exhibit no detectable CDC activities. In some embodiments, the reduction
and/or abatement
of CDC activity may be attributed to the reduced affinity antibodies of the
invention exhibit
for Fc ligands and/or receptors. Measurement of effector function may be
performed as
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described in Example 3.
[00181] In some embodiments, antibodies comprising Fe regions described herein
exhibit
decreased affinities to Clq relative to an unmodified antibody (e.g, human
IgG1 having SEQ
ID NO: 320). In some embodiments, antibodies herein exhibit affinities for Clq
receptor that
are at least 2 fold, or at least 3 fold, or at least 5 fold, or at least 7
fold, or at least 10 fold, or
at least 20 fold, or at least 30 fold, or at least 40 fold, or at least 50
fold, or at least 60 fold, or
at least 70 fold, or at least 80 fold, or at least 90 fold, or at least 100
fold, or at least 200 fold
less than an unmodified antibody. In some embodiments, antibodies herein
exhibit affinities
for Clq that are at least 90%, at least 80%, at least 70%, at least 60%, at
least 50%, at least
40%, at least 30%, at least 20%, at least 10%, or at least 5% less than an
unmodified
antibody.
1001821 In some embodiments, the antibodies of this disclosure are variants
that possess
some but not all effector functions, which make it a desirable candidate for
applications in
which the half-life of the antibody in vivo is important yet certain effector
functions (such as
complement and ADCC) are unnecessary or deleterious.
[00183] In vitro and/or in vivo cytotoxicity assays can be conducted to
confirm the
reduction/depletion of CDC and/or ADCC activities. For example, Fe receptor
(FcR) binding
assays can be conducted to ensure that the antibody lacks FcyR binding (hence
likely lacking
ADCC activity) but retains FcRn binding ability. Measurement of effector
function may be
performed as described in Example 3.
1001841 In some embodiments, antibodies are tested for binding to Fey
receptors and
complement Clq by ELISA. In some embodiments, antibodies are tested for the
ability to
activate primary human immune cells in vitro, for example, by assessing their
ability to
induce expression of activation markers.
[00185] In some embodiments, assessment of ADCC activity of an anti-TL1A
antibody
comprises adding the antibody to target cells in combination with immune
effector cells,
which may be activated by the antigen antibody complexes resulting in
cytolysis of the target
cell. Cytolysis may be detected by the release of lab el (e.g. radioactive
substrates, fluorescent
dyes or natural intracellular proteins) from the lysed cells. Useful effector
cells for such
assays include peripheral blood mononuclear cells (PBMC) and Natural Killer
(NK) cells.
Specific examples of in vitro ADCC assays are described in Wisecarver et al.,
1985 79:277-
282; Bruggemann et al., 1987, J Exp Med 166:1351-1361; Wilkinson et al., 2001,
J Immunol
Methods 258:183-191; Patel et al., 1995 J Immunol Methods 184:29-38.
Alternatively, or
additionally, ADCC activity of the antibody of interest may be assessed in
vivo, e.g., in an
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animal model such as that disclosed in Clynes et al., 1998, PNAS USA 95:652-
656.
[00186] In some embodiments, an assessment of complement activation, a CDC
assay,
may be performed as described in Gazzano-Santoro et al., 1996, J. Immunol.
Methods,
202:163.
[00187] Non-limiting examples of Fc mutations in IgG1 that may reduce ADCC
and/or
CDC include substitutions at one or more of positions: 231, 232, 234, 235,
236, 237, 238,
239, 264, 265, 267, 269, 270, 297, 299,318,320,322,325,327, 328,329,330, and
331 in
IgGl, where the numbering system of the constant region is that of the EU
index as set forth
by Kabat. In certain embodiments, the antibodies of this disclosure have
reduced effector
function as compared with human IgGl.
[00188] In some embodiments, an antibody comprises an IgG1 Fc
region comprising one
or more of the following substitutions according to the Kabat numbering
system: N297A,
N297Q, N297D, D265A, S228P, L235A, L237A, L234A, E233P, L234V, C236 deletion,
P238A, A327Q, P329A, P329G, L235E, P33 1S, L234F, 235G, 235Q, 235R, 235S,
236F,
236R, 237E, 237K, 237N, 237R, 238A, 238E, 238G, 238H, 2381, 238V, 238W, 238Y,
248A,
254D, 254E, 254G, 254H, 2541, 254N, 254P, 254Q, 254T, 254V, 255N, 256H, 256K,
256R,
256V, 264S, 265H, 265K, 265S, 265Y, 267G, 267H, 2671, 267K, 268K, 269N, 269Q,
270A,
270G, 270M, 270N, 271T, 272N, 279F, 279K, 279L, 292E, 292F, 292G, 2921, 293S,
301W,
304E, 311E, 311G, 311S, 316F, 3271, 328V, 329Y, 330R, 339E, 339L, 3431, 343V,
373A,
373G, 373S, 376E, 376W, 376Y, 380D, 382D, 382P, 385P, 424H, 424M, 424V, 4341,
438G,
439E, 439H, 439Q, 440A, 440D, 440E, 440F, 440M, 440T, 440V.
[00189] In some embodiments, an antibody comprises a Fc region selected from
the
representative sequences disclosed in Table 3, Table 13, and Table 9B. In some
embodiments, an antibody comprises an IgG1 Fc region comprising E233P,
according to the
Kabat numbering system. In some embodiments, an antibody comprises an IgG4 Fc
region
comprising S228P and L23 5E. In some embodiments, an antibody comprises an
IgG1 Fc
region comprising L23 5E, according to the Kabat numbering system. In some
embodiments,
an antibody comprises an IgG1 Fc region comprising L234A and L235A, according
to the
Kabat numbering system. In some embodiments, an antibody comprises an IgG1 Fc
region
comprising L234A, L235A, and G237A, according to the Kabat numbering system.
In some
embodiments, an antibody comprises an IgG1 Fc region comprising L234A, L235A,
P329G,
according to the Kabat numbering system. In some embodiments, an antibody
comprises an
IgG1 Fc region comprising L234F, L235E, and P331 S, according to the Kabat
numbering
system. In some embodiments, an antibody comprises an IgG1 Fc region
comprising L234A,
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L235E, and G237A, according to the Kab at numbering system. In some
embodiments, an
antibody comprises an IgG1 Fe region comprising L234A, L235E, G237A, and
P331S,
according to the Kabat numbering system. In some embodiments, an antibody
comprises an
IgG1 Fe region comprising L234A, L235A, G237A, P238S, H268A, A330S, and P331S
(IgG1 (5), according to the Kabat numbering system. In some embodiments, an
antibody
comprises an IgG1 Fe region comprising L234A, L23 5A, and P329A, according to
the Kabat
numbering system. In some embodiments, an antibody comprises an IgG1 Fe region
comprising G23 6R and L328R, according to the Kab at numbering system. In some
embodiments, an antibody comprises an IgG1 Fe region comprising G237A,
according to the
Kabat numbering system. In some embodiments, an antibody comprises an IgG1 Fe
region
comprising F241A, according to the Kabat numbering system. In some
embodiments, an
antibody comprises an IgG1 Fe region comprising V264A, according to the Kabat
numbering
system. In some embodiments, an antibody comprises an IgG1 Fe region
comprising D265A,
according to the Kabat numbering system. In some embodiments, an antibody
comprises an
IgG1 Fe region comprising D265A and N297A, according to the Kabat numbering
system. In
some embodiments, an antibody comprises an IgG1 Fe region comprising D265A and
N297G, according to the Kabat numbering system. In some embodiments, an
antibody
comprises an IgG1 Fe region comprising D270A, according to the Kabat numbering
system.
In some embodiments, an antibody comprises an IgG1 Fe region comprising N297A,
according to the Kabat numbering system. In some embodiments, an antibody
comprises an
IgG1 Fe region comprising N297G, according to the Kabat numbering system. In
some
embodiments, an antibody comprises an IgG1 Fe region comprising N297D,
according to the
Kabat numbering system. In some embodiments, an antibody comprises an IgG1 Fe
region
compri sing N297Q, according to the Kabat numbering system. In some
embodiments, an
antibody comprises an IgG1 Fe region comprising P329A, according to the Kabat
numbering
system. In some embodiments, an antibody comprises an IgG1 Fe region
comprising P329G,
according to the Kabat numbering system. In some embodiments, an antibody
comprises an
IgG1 Fe region comprising P329R, according to the Kabat numbering system. In
some
embodiments, an antibody comprises an IgG1 Fe region comprising A330L,
according to the
Kabat numbering system. In some embodiments, an antibody comprises an IgG1 Fe
region
comprising P33 1A, according to the Kabat numbering system. In some
embodiments, an
antibody comprises an IgG1 Fe region comprising P3315, according to the Kabat
numbering
system. In some embodiments, an antibody comprises an IgG2 Fe region. In some
embodiments, an antibody comprises an IgG4 Fe region. In some embodiments, an
antibody
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comprises an IgG4 Fc region comprising S228P, according to the Kabat numbering
system.
In some embodiments, an antibody comprises an IgG4 Fe region comprising S228P,
F234A,
and L23 5A, according to the Kabat numbering system. In some embodiments, an
antibody
comprises an IgG2-IgG4 cross-subclass (IgG2/G4)Fc region. In some embodiments,
an
antibody comprises an IgG2-IgG3 cross-subclass Fc region. In some embodiments,
an
antibody comprises an IgG2 Fc region comprising H268Q, V309L, A330S, and P33
is,
according to the Kabat numbering system. In some embodiments, an antibody
comprises an
IgG2 Fc region comprising V234A, G237A, P238S, H268A, V309L, A3305, and P331S,
according to the Kabat numbering system. In some embodiments, an antibody
comprises a Fc
region comprising high mannose glycosylation.
1001901 In some embodiments, an antibody comprises an IgG4 Fc region
comprising a
S228P substitution, according to the Kabat numbering system. In some
embodiments, an
antibody comprises an IgG4 Fc region comprising an A330S substitution,
according to the
Kabat numbering system. In some embodiments, an antibody comprises an IgG4 Fc
region
comprising a P33 1S substitution, according to the Kabat numbering system.
1001911 In some embodiments, an antibody comprises an IgG2 Fc region
comprising an
A330S substitution, according to the Kabat numbering system. In some
embodiments, an
antibody comprises an IgG2 Fc region comprising an P33 1S substitution,
according to the
Kabat numbering system. In some embodiments, an antibody comprises an IgG2 Fc
region
comprising an 234A substitution, according to the Kabat numbering system. In
some
embodiments, an antibody comprises an IgG2 Fc region comprising an 237A
substitution,
according to the Kabat numbering system.
1001921 In certain embodiments, an anti-TL1A described herein comprises a Fc
region as
shown in Table 13.
Table 13. Exemplary Fe Mutations
Constant Region (SEQ ID NO)
Mutations
K DL R EM K EM
Wild-type IgG1 320 321 322
L235E 323 324 325
L234A, L235A 326 327 328
L234A, L235A, G237A 329 330 331
L234A, L235A, P329G 332 333 334
L234F, L235E, P331S 335 336 337
L234A, L235E, G237A 338 339 340
L234A, L235E, G237A, P331S 341 342 343
L234A, L235A, P329A 344 345 346
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D265A 347 348 349
N297G 350 351 352
D265A, N297A 353 354 355
D265A, N297G 356 357 358
L235A, G237A 359 360 361
Wild-type IgG4 362
1001931 In certain embodiments, an anti-TLIA antibody described herein
comprises a Fc
region comprising a sequence from Table 9B. In certain embodiments, an anti-
TL1A
antibody described herein comprises a Fc region comprising any one of SEQ ID
NOS: 320-
367 or a sequence at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,
or 99%
identical to any one of SEQ ID NOS: 320-367.
1001941 In some embodiments, anti-TL1A described herein comprise a light chain
constant region comprising SEQ ID NO: 319 or a sequence at least about 90%,
91%, 92%,
93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 319.
1001951 Additional Non-limiting Example anti-TL1A Antibody Embodiments
01961 CDR Embodiments
1001971 In one aspect, provided herein is a first embodiment of an anti-TLIA
antibody. As
used herein, an anti-TLIA antibody includes an anti-TLIA antigen binding
fragment. Non-
limiting additional embodiments include: (Embodiment 2) The anti-TLIA antibody
of
embodiment 1, comprising a heavy chain comprising a HCDRI, a HCDR2, and a
HCDR3,
and a light chain comprising a LCDR1, a LCDR2, and a LCDR3. (Embodiment 3) The
anti-
TL1A antibody of embodiment 1, comprising a HCDR1 comprising SEQ ID NO: 1.
(Embodiment 4) The anti-TLIA antibody of embodiment 1 or embodiment 2,
comprising a
HCDR2 comprising SEQ ID NO: 2. (Embodiment 5) The anti-TL1A antibody of
embodiment 1 or embodiment 2, comprising a HCDR2 comprising SEQ ID NO: 3.
(Embodiment 6) The anti-TL1A antibody of embodiment 1 or embodiment 2,
comprising a
HCDR2 comprising SEQ ID NO: 4. (Embodiment 7) The anti-TLIA antibody of
embodiment 1 or embodiment 2, comprising a HCDR2 comprising SEQ ID NO: 5.
(Embodiment 8) The anti-TL1A antibody of any one of embodiments 1-6,
comprising a
HCDR3 comprising SEQ ID NO: 6. (Embodiment 9) The anti-TLIA antibody of any
one of
embodiments 1-6, comprising a HCDR3 comprising SEQ ID NO: 7. (Embodiment 10)
The
anti-TLIA antibody of any one of embodiments 1-6, comprising a HCDR3
comprising SEQ
ID NO: 8. (Embodiment 11) The anti-TL1A antibody of any one of embodiments 1-
6,
comprising a HCDR3 comprising SEQ ID NO: 9. (Embodiment 12) The anti-TLIA
antibody
of any one of embodiments 1-10, comprising a LCDRI comprising SEQ ID NO: 10.
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(Embodiment 13) The anti-TL1A antibody of any one of embodiments 1-11,
comprising a
LCDR2 comprising SEQ ID NO: 11. (Embodiment 14) The anti-TL1A antibody of any
one
of embodiments 1-12, comprising a LCDR3 comprising SEQ ID NO: 12. (Embodiment
15)
The anti-TL1A antibody of any one of embodiments 1-12, comprising a LCDR3
comprising
SEQ ID NO: 13. (Embodiment 16) The anti-TL1A antibody of any one of
embodiments 1-12,
comprising a LCDR3 comprising SEQ ID NO: 14 or 15. (Embodiment 17) the anti-
TL1A
antibody of embodiment 1, comprising the CDRs of antibody A, B, C, D, E, F, G,
H, I, A2,
B2, C2, D2, E2, F2, G2, H2, or 12 (Table 10). (Embodiment 18) The anti-TL1A
antibody of
embodiment 1, comprising a heavy chain variable region comprising: (a) an
HCDR1
comprising an amino acid sequence set forth by SEQ ID NO: 1; (b) an HCDR2
comprising an
amino acid sequence set forth by any one of SEQ ID NOS: 2-5; and (c) an HCDR3
comprising an amino acid sequence set forth by any one of SEQ ID NOS: 6-9; and
the light
chain variable region comprises: (d) an LCDR1 comprising an amino acid
sequence set forth
by SEQ ID NO: 10; (e) an LCDR2 comprising an amino acid sequence set forth by
SEQ ID
NO: 11; and (f) an LCDR3 comprising an amino acid sequence set forth by any
one of SEQ
ID NOS: 12-15. (Embodiment 19) The anti-TL1 A antibody of embodiment 1,
comprising a
HCDR1 as set forth by SEQ ID NO: 1, a HCDR2 as set forth by SEQ ID NO: 2, a
HCDR3 as
set forth by SEQ ID NO: 6, a LCDR1 as set forth by SEQ ID NO: 10, a LCDR2 as
set forth
by SEQ ID NO: 11, and a LCDR3 as set forth by SEQ ID NO: 12
[00198] Framework Embodiments
[00199] (Embodiment 20) The anti-TL1A antibody of any one of embodiments 1-19,
comprising a heavy chain framework comprising IGHV1-46*02. (Embodiment 21) The
anti-
TL1A antibody of any one of embodiments 1-19, comprising a heavy chain
framework
comprising a variant of IGHV1-46*02 comprising between about 1 and about 20
amino acid
substitutions from SEQ ID NO: 316. (Embodiment 22) The anti-TL1A antibody of
any one
of embodiments 1-19, comprising a heavy chain framework comprising a variant
of IGHV1-
46*02 comprising between about 1 and about 9 amino acid substitutions from SEQ
ID NO:
316. (Embodiment 23) The anti-TL1A antibody of any one of embodiments 1-19,
comprising
a heavy chain framework comprising a variant of IGHV1-46*02 comprising about
1, 2, 3, 4,
5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17,18, 19, or 20 amino acid
substitutions from SEQ
ID NO: 316 in the framework. (Embodiment 24) The anti-TL1A antibody of any one
of
embodiments 21-23, wherein the heavy chain framework substitution comprises Q1
E, as
determined by Aho or Kab at numbering. (Embodiment 25) The anti-TL1A antibody
of any
one of embodiments 21-24, wherein the heavy chain framework substitution
comprises
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R45K, as determined by Aho or Kabat numbering. (Embodiment 26) The anti-TLI A
antibody of any one of embodiments 21-25, wherein the heavy chain framework
substitution
comprises A47R, as determined by Aho or Kab at numbering. (Embodiment 27) The
anti-
TLIA antibody of any one of embodiments 21-26, wherein the heavy chain
framework
substitution comprises M5 51, as determined by Aho or Kab at numbering.
(Embodiment 28)
The anti-TLIA antibody of any one of embodiments 21-27, wherein the heavy
chain
framework substitution comprises V78A, as determined by Aho or Kab at
numbering.
(Embodiment 29) The anti-TLIA antibody of any one of embodiments 21-28,
wherein the
heavy chain framework substitution comprises M80I, as determined by Aho or Kab
at
numbering. (Embodiment 30) The anti-TLIA antibody of any one of embodiments 21-
29,
wherein the heavy chain framework substitution comprises R82T, as determined
by Aho or
Kab at numbering. (Embodiment 31) The anti-TL1A antibody of any one of
embodiments 21-
30, wherein the heavy chain framework substitution comprises V89A, as
determined by Aho
or Kab at numbering. (Embodiment 32) The anti-TLIA antibody of any one of
embodiments
21-31, wherein the heavy chain framework substitution comprises M91L, as
determined by
Aho or Kabat numbering.
1002001 (Embodiment 33) The anti-TLIA antibody of any one of embodiments 1-19,
comprising a heavy chain framework comprising SEQ ID NO: 301. (Embodiment 34)
The
anti-TLIA antibody of embodiment 33, wherein XI is Q. (Embodiment 35) The anti-
TLIA
of embodiment 33, wherein XI = E. (Embodiment 36) The anti-TLIA of any one of
embodiments 33-35, wherein X2 = R. (Embodiment 37) The anti-TLIA of any one of
embodiments 33-35, wherein X2 = K. (Embodiment 38) The anti-TLIA of any one of
embodiments 33-37, wherein X3 = A. (Embodiment 39) The anti-TLIA of any one of
embodiments 33-37, wherein X3 =R. (Embodiment 40) The anti-TL1A of any one of
embodiments 33-39, wherein X4 =M. (Embodiment 41) The anti-TLIA of any one of
embodiments 33-39, wherein X4 =1. (Embodiment 42) The anti-TL1A of any one of
embodiments 33-41, wherein X5 =V. (Embodiment 43) The anti-TLIA of any one of
embodiments 33-41, wherein X5 =A. (Embodiment 44) The anti-TLIA of any one of
embodiments 33-43, wherein X6 =M. (Embodiment 45) The anti-TLIA of any one of
embodiments 33-43, wherein X6 =1. (Embodiment 46) The anti-TL1A of any one of
embodiments 33-45, wherein X7 = R. (Embodiment 47) The anti-TLI A of any one
of
embodiments 33-45, wherein X7 = T. (Embodiment 48) The anti-TLIA of any one of
embodiments 33-47, wherein X8 =V. (Embodiment 49) The anti-TLIA of any one of
embodiments 33-47, wherein X8 =A. (Embodiment 50) The anti-TLIA of any one of
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embodiments 33-49, wherein X9 =M. (Embodiment 51) The anti-TLIA of any one of
embodiments 33-49, wherein X9 =L.
[00201] (Embodiment 52) The anti-TLIA antibody of any one of embodiments 1-51,
comprising a light chain framework comprising IGKV3-20*01. (Embodiment 53) The
anti-
TLIA antibody of any one of embodiments 1-51, comprising a light chain
framework
comprising a variant of IGKV3-20*01 comprising between about 1 and about 20
amino acid
substitutions from SEQ ID NO: 317. (Embodiment 54) The anti-TL1A antibody of
any one
of embodiments 1-51, comprising a light chain framework comprising a variant
of IGKV3-
20*01 comprising about 1 amino acid substitution from SEQ ID NO: 317.
(Embodiment 55)
The anti-TLIA antibody of any one of embodiments 1-51, comprising a light
chain
framework comprising a variant of IGKV3-20*01 comprising about 2 amino acid
substitutions from SEQ ID NO: 317. (Embodiment 56) The anti-TL1A antibody of
any one
of embodiments 1-51, comprising a light chain framework comprising a variant
of IGKV3-
20*01 comprising about I, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12,13, 14,15, 16,17,
18,19, or 20
amino acid substitutions from SEQ ID NO: 317 in the framework. (Embodiment 57)
The
anti-TL1A antibody of any one of embodiments 53-56, wherein the light chain
framework
substitution comprises Q1E, as determined by Aho or Kabat numbering.
(Embodiment 58)
The anti-TLIA antibody of any one of embodiments 53-57, wherein the light
chain
framework substitution comprises R45K, as determined by Aho or Kabat
numbering.
[00202] (Embodiment 59) The anti-TLIA antibody of any one of embodiments 1-51,
comprising a light chain comprising a light chain framework comprising SEQ ID
NO: 303.
(Embodiment 60) The anti-TLIA antibody of embodiment 59, wherein X10 is L.
(Embodiment 61) The anti-TLIA antibody of embodiment 59, wherein X10 is P.
(Embodiment 62) The anti-TL1A antibody of any one of embodiments 59-61,
wherein X11 is
L. (Embodiment 63) The anti-TLIA antibody of any one of embodiments 59-61,
wherein
X11 is W.
[00203] (Embodiment 64) The anti-TLIA antibody of any one of embodiments 1-19,
comprising a heavy chain variable framework region comprising a modified human
IGHV1-
46*02 framework, and a light chain variable framework region comprising a
human IGKV3 -
20 framework or a modified human IGKV3-20 framework, wherein the heavy chain
variable
framework region and the light chain variable framework region collectively
comprise at
least one amino acid modification(s) as compared to the human IGHV1-46*02
framework
and the human IGKV3-20 framework. (Embodiment 65) The antibody of embodiment
64,
wherein the at least one amino acid modification(s) is no more than about 13,
12, 11, 10, 9, or
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8 amino acid modifications. (Embodiment 66) The antibody of embodiment 64 or
embodiment 65, wherein the amino acid modification(s) comprise: a modification
at amino
acid position 45 in the heavy chain variable region. (Embodiment 67) The
antibody of any
one of embodiments 64-66, wherein the amino acid modification(s) comprise a
modification
at amino acid position 47 in the heavy chain variable region. (Embodiment 68)
The antibody
of any one of embodiments 64-67, wherein the amino acid modification(s)
comprise a
modification at amino acid position 55 in the heavy chain variable region.
(Embodiment 69)
The antibody of any one of embodiments 64-68, wherein the amino acid
modification(s)
comprise a modification at amino acid position 78 in the heavy chain variable
region.
(Embodiment 70) The antibody of any one of embodiments 64-69, wherein the
amino acid
modification(s) comprise a modification at amino acid position 80 in the heavy
chain variable
region. (Embodiment 71) The antibody of any one of embodiments 64-70, wherein
the amino
acid modification(s) comprise a modification at amino acid position 82 in the
heavy chain
variable region. (Embodiment 72) The antibody of any one of embodiments 64-71,
wherein
the amino acid modification(s) comprise a modification at amino acid position
89 in the
heavy chain variable region. (Embodiment 73) The antibody of any one of
embodiments 64-
72, wherein the amino acid modification(s) comprise a modification at amino
acid position 91
in the heavy chain variable region, per Aho or Kabat numbering. (Embodiment
74) The
antibody of any one of embodiments 64-65, wherein the amino acid
modification(s) comprise
(a) R45K, (b) A47R, (c) M551, (d) V78A, (e) M801, (f) R82T, (g) V89A, or (h)
M91L in the
heavy chain variable region, per Aho or Kab at numbering; or a combination of
two or more
modifications selected from (a) to (h). (Embodiment 75) The antibody of
embodiment 74,
wherein the amino acid modification(s) comprise: A47R. (Embodiment 76) The
antibody of
embodiment 74, wherein the amino acid modification(s) comprise: A47R, M55I,
V78A,
M80I, R82T, V89A, and M91L; A47R, M80I, and R82T; A47R, M80I, R82T, V89A, and
M91L; or A47R, M55I, V78A, M80I, V89A, and M91L. (Embodiment 77) The antibody
of
embodiment 74, wherein the amino acid modification(s) comprise: R45K and A47R.
(Embodiment 78) The antibody of embodiment 74, wherein the amino acid
modification(s)
comprise: R45K, A47R, V89A, and M91L. (Embodiment 79) The antibody of
embodiment
74, wherein the amino acid modification(s) comprise: R45K and A47R, and M80I.
(Embodiment 80) The antibody of embodiment 74, wherein the amino acid
modification(s)
comprise: R45K, A47R, M80I, and M91L; R45K, A47R, V78A, M80I, V89A, and M91L;
R45K, A47R, M55I, V78A, M80I, R82T, V89A, and M91L; R45K, A47R, M80I, V89A,
and
M91L; R45K, A47R, M55I, M80I, R82T, V89A, and M91L; R45K, A47R, M80I, and
V89A;
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R45K, A47R, M80I, R82T, V89A, M91L; or R45K, A47R, M55I, M80I, V89A, and M91L.
(Embodiment 81) The antibody of embodiment 74, wherein the amino acid
modification(s)
comprise: R45K. (Embodiment 82) The antibody of embodiment 74, wherein the
amino acid
modification(s) comprise: R45K and V78A. (Embodiment 83) The antibody of
embodiment
74, wherein the amino acid modification(s) comprise: V78A. (Embodiment 84) The
antibody
of embodiment 74, wherein the amino acid modification(s) comprise: V78A and
V89A;
V78A and M80I; or V78A, M80I, and R82T. (Embodiment 85) The antibody of
embodiment
74, wherein the amino acid modification(s) comprise: V89A. (Embodiment 86) The
antibody
of embodiment 74, wherein the amino acid modification(s) comprise: M80I.
(Embodiment
87) The antibody of any one of embodiments 64-86, wherein the amino acid
modification(s)
comprises: (a) a modification at amino acid position 54 in the light chain
variable region;
and/or (b) a modification at amino acid position 55 in the light chain
variable region, per Aho
or Kab at numbering. (Embodiment 88) The antibody of embodiment 87, wherein
the amino
acid modification(s) comprises L54P in the light chain variable region, per
Aho or Kab at
numbering. (Embodiment 89) The antibody of embodiment 87 or 88, wherein the
amino acid
modification(s) comprises L5 SW in the light chain variable region, per Aho or
Kabat
numbering.
1002041 (Embodiment 90) The antibody of any one of embodiments 1-19,
comprising a
heavy chain FR1 as set forth by SEQ ID NO: 304. (Embodiment 91) The antibody
of any one
of embodiments 1-19 or 90, comprising a heavy chain FR2 as set forth by SEQ ID
NO: 305.
(Embodiment 92) The antibody of any one of embodiments 1-19 or 90, comprising
a heavy
chain FR2 as set forth by SEQ ID NO: 313. (Embodiment 93) The antibody of any
one of
embodiments 1-19 or 90-92, comprising a heavy chain FR3 as set forth by SEQ ID
NO: 306.
(Embodiment 94) The antibody of any one of embodiments 1-19 or 90-92,
comprising a
heavy chain FR3 as set forth by SEQ ID NO: 307. (Embodiment 95) The antibody
of any one
of embodiments 1-19 or 90-92, comprising a heavy chain FR3 as set forth by SEQ
ID NO:
314. (Embodiment 96) The antibody of any one of embodiments 1-19 or 90-92,
comprising a
heavy chain FR3 as set forth by SEQ ID NO: 315. (Embodiment 97) The antibody
of any one
of embodiments 1-19 or 90-96, comprising a heavy chain FR4 as set forth by SEQ
ID NO:
308. (Embodiment 98) The antibody of any one of embodiments 1-19 or 90-97,
comprising a
light chain FR1 as set forth by SEQ ID NO: 309. (Embodiment 99) The antibody
of any one
of embodiments 1-19 or 90-98, comprising a light chain FR2 as set forth by SEQ
ID NO:
310. (Embodiment 100) The antibody of any one of embodiments 1-19 or 90-99,
comprising
a light chain FR3 as set forth by SEQ ID NO: 311. (Embodiment 101) The
antibody of any
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one of embodiments 1-19 or 90-100, comprising a light chain FR4 as set forth
by SEQ ID
NO: 312. (Embodiment 102) The antibody of any one of embodiments 1-19,
comprising a
HC FR1 as set forth by SEQ ID NO: 304, a HC FR2 as set forth by SEQ ID NO:
305, a HC
FR3 as set forth by SEQ ID NO: 307, a HC I-,R4 as set forth by SEQ ID NO: 308,
a LC FR1
as set forth by SEQ ID NO: 309, a LC FR2 as set forth by SEQ ID NO: 310, a LC
FR3 as set
forth by SEQ ID NO: 311, and a LC FR4 as set forth by SEQ ID NO: 312.
[00205] Variable Region Embodiments
[00206] (Embodiment 103) The antibody of embodiment 1, comprising a heavy
chain
variable domain comprising an amino acid sequence at least about 80%, 81%,
82%, 83%,
84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,
99%,
or 100% identical to any one of SEQ ID NOS: 101-169, and a light chain
variable domain
comprising an amino acid sequence at least about 80%, 81%, 82%, 83%, 84%, 85%,
86%,
87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical
to any one of SEQ ID NOS: 201-220. (Embodiment 104) The antibody of embodiment
103,
comprising a heavy chain variable domain comprising an amino acid sequence at
least 96%
identical to SEQ ID NO: 104, and a light chain variable domain comprising an
amino acid
sequence at least 97% identical to SEQ ID NO: 201. (Embodiment 105) The
antibody of
embodiment 103, comprising an amino acid sequence at least 97% identical to
SEQ ID NO:
104. (Embodiment 106) The antibody of embodiment 103, comprising an amino acid
sequence at least 98% identical to SEQ ID NO: 104. (Embodiment 107) The
antibody of
embodiment 103, comprising an amino acid sequence at least 99% identical to
SEQ ID NO:
104. (Embodiment 108) The antibody of embodiment 103, comprising SEQ ID NO:
104.
(Embodiment 109) The antibody of any one of embodiments 103-108, comprising an
amino
acid sequence at least 98% identical to SEQ ID NO: 201. (Embodiment 110) The
antibody of
embodiment 109, comprising an amino acid sequence at least about 99% identical
to SEQ ID
NO: 201. (Embodiment 111) The antibody of embodiment 109, comprising SEQ ID
NO: 201.
[00207] (Embodiment 112) The antibody of embodiment 103, comprising a heavy
chain
variable domain comprising an amino acid sequence at least about 97% identical
to SEQ ID
NO: 104, and alight chain variable domain comprising an amino acid sequence at
least about
97% identical to SEQ ID NO: 201. (Embodiment 113) The antibody of embodiment
112,
wherein the heavy chain variable domain comprises an amino acid sequence at
least about
98% identical to SEQ ID NO: 104. (Embodiment 114) The antibody of embodiment
112,
wherein the heavy chain variable domain comprises an amino acid sequence at
least about
99% identical to SEQ ID NO: 104. (Embodiment 115) The antibody of embodiment
112,
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wherein the heavy chain variable domain comprises SEQ ID NO: 104. (Embodiment
116)
The antibody of any one of embodiments 112-115, wherein the light chain
variable domain
comprises an amino acid sequence at least about 98% identical to SEQ ID NO:
201.
(Embodiment 117) The antibody of any one of embodiments 112-116, wherein the
light chain
variable domain comprises an amino acid sequence at least about 99% identical
to SEQ ID
NO: 201. (Embodiment 118) The antibody of any one of embodiments 112-117,
wherein the
light chain variable domain comprises SEQ ID NO: 201.
[00208] Fc region Embodiments
[00209] (Embodiment 119) The antibody of any one of embodiments 1-118,
comprising a
fragment crystallizable (Fc) region. (Embodiment 120) The antibody of
embodiment 119,
comprising reduced antibody-dependent cell-mediated cytotoxicity (ADCC)
function as
compared to human IgG1 and/or reduced complement-dependent cytotoxicity (CDC)
as
compared to human IgGl. (Embodiment 121) The antibody of embodiment 120,
wherein the
human IgG1 comprises SEQ ID NO. 320. (Embodiment 122) The antibody of
embodiment
120 or embodiment 121, wherein the ADCC function of the Fc region comprising
reduced
ADCC is at least about 50% reduced as compared to human IgGl. (Embodiment 123)
The
antibody of any one of embodiments 120-122, wherein the CDC function of the Fc
region
comprising reduced ADCC is at least about 50% reduced as compared to human
IgGl.
(Embodiment 124) The anti-TL1A antibody of any one of embodiments 119-123,
comprising
a human IgG1 Fc region comprising (a) 297A, 297Q, 297G, or 297D, (b) 279F,
279K, or
279L, (c) 228P, (d) 235A, 235E, 235G, 235Q, 235R, or 235S, (e) 237A, 23 IL,
237K, 237N,
or 237R, (f) 234A, 234V, or 234F, (g) 233P, (h) 328A, (i) 327Q or 327T, (j)
329A, 329G,
329Y, or 329R (k) 331S, (1) 236F or 236R, (m) 238A, 238E, 238G, 238H, 2381,
238V,
238W, or 238Y, (n) 248A, (o) 254D, 254E, 254G, 254H, 2541, 254N, 254P, 254Q,
254T, or
254V, (p) 255N, (q) 256H, 256K, 256R, or 256V, (r) 264S, (s) 265H, 265K, 265S,
265Y, or
265A, (t) 267G, 267H, 2671, or 267K, (u) 268K, (v) 269N or 269Q, (w) 270A,
270G, 270M,
or 270N, (x) 271T, (y) 272N, (z) 292E, 292F, 292G, or 2921, (aa) 293S, (bb)
301W, (cc)
304E, (dd) 311E, 311G, or 311S, (ee) 316F, (ff) 328V, (gg) 330R, (hh) 339E or
339L, (ii)
3431 or 343V, (jj) 373A, 373G, or 373S, (kk) 376E, 376W, or 376Y, (11) 380D,
(mm) 382D
or 382P, (nn) 385P, (oo) 424H, 424M, or 424V, (pp) 4341, (qq) 438G, (rr) 439E,
439H, or
439Q, (ss) 440A, 440D, 440E, 440F, 440M, 440T, or 440V, (tt) E233P, (uu)
L235E, (vv)
L234A and L235A, (ww) L234A, L235A, and G237A, (xx) L234A, L235A, and P329G,
(yy)
L234F, L235E, and P33 1S, (zz) L234A, L235E, and G237A, (aaa), L234A, L235E,
G237A,
and P331S (bbb) L234A, L235A, G237A, P238S, H268A, A330S, and P331 S (IgG1 a),
(ccc)
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L234A, L235A, and P329A, (ddd) G236R and L328R, (eee) G237A, (fff)F241A, (ggg)
V264A, (hhh) D265A, (iii) D265A and N297A, (jjj) D265A and N297G, (kkk) D270A,
(111)
A3 30L, (mmm)P331A or P331 S, or (nnn) any combination of (a) - (uu), per Kab
at
numbering. (Embodiment 125) The anti-TLIA of any one of embodiments 119-123,
comprising a (i) human IgG4 Fc region or (ii) a human IgG4 Fc region
comprising (a) S228P,
(b) S228P and L23 5E, or (c) S228P, F234A, and L23 5A, per Kab at numbering.
(Embodiment
126) The anti-TL1A of any one of embodiments 119-123, comprising a human IgG2
Fc
region; IgG2-IgG4 cross-subclass Fc region; IgG2-IgG3 cross-subclass Fc
region; IgG2
comprising H268Q, V309L, A330S, P331S (IgG2m4); or IgG2 comprising V234A,
G237A,
P238S, H268A, V309L, A330S, P33 1S (IgG2a). (Embodiment 127) The antibody of
any one
of embodiments 119-123, comprising a human IgG1 comprising one or more
substitutions
selected from the group comprising 329A, 329G, 329Y, 331S, 236F, 236R, 238A,
238E,
238G, 238H, 2381, 238V, 238W, 238Y, 248A, 254D, 254E, 254G, 254H, 2541, 254N,
254P,
254Q, 254T, 254V, 264S, 265H, 265K, 265S, 265Y, 265A, 267G, 267H, 2671, 267K,
4341,
438G, 439E, 439H, 439Q, 440A, 440D, 440E, 440F, 440M, 440T, and 440V, per
Kabat
numbering. (Embodiment 128) The anti-TLI A of any one of embodiments 119-123,
comprising a heavy chain Fc region comprising a sequence at least about 80%,
81%, 82%,
83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,
98%,
99%, or 100% identical to any one of SEQ ID NOS: 320-362. (Embodiment 129) The
anti-
TL1A of any one of embodiments 119-123, comprising a heavy chain Fc region
comprising a
sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%,
91%,
92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to any one of SEQ ID
NOS:
368-380. (Embodiment 130) The anti-TLI A of any one of embodiments 119-123,
comprising
a constant region comprising a sequence at least about 80%, 81%, 82%, 83%,
84%, 85%,
86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical to SEQ ID NO: 381.
[00210] Additional antibody features
[00211] (Embodiment 131) The anti-TLI A antibody of any one of embodiments 1-
130,
comprising a light chain constant region comprising a sequence at least about
80%, 81%,
82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%,
97%,
98%, 99%, or 100% identical to SEQ ID NO: 319.
[00212] (Embodiment 132) The anti-TL1A antibody of any one of embodiments 1-
131,
comprising at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%,
90%,
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91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% monomeric fraction as
determined by
size exclusion chromatography. (Embodiment 133) , The antibody of embodiment
132,
wherein the size exclusion chromatography comprises injecting purified
antibody onto a size
exclusion column, wherein the antibody is purified by protein A. (Embodiment
134) The
antibody of embodiment 132 or 133, wherein the antibody is purified as
described in
Example 2. (Embodiment 135) The antibody of any one of embodiments 132-134,
wherein
the antibody is expressed under conditions described in Example 2. (Embodiment
136) The
antibody of any one of embodiments 132-135, wherein the size exclusion
chromatography
column has an inner diameter of 4.6 mm. (Embodiment 137) The antibody of any
one of
embodiments 132-136, wherein the size exclusion chromatography column has a
length of
150 mm. (Embodiment 138) The antibody of any one of embodiments 132-137,
wherein the
size exclusion chromatography column has a pore size of 200 A. (Embodiment
139) The
antibody of any one of embodiments 132-138, wherein the size exclusion
chromatography
column has a particle size of 1.7 micrometer. (Embodiment 140) The antibody of
any one of
embodiments 132-139, wherein the size exclusion chromatography column is
ACQUITY
UPLC BEH200 SEC column (Embodiment 141) The antibody of any one of embodiments
132-140, wherein the antibody or antigen binding fragment is injected at a
total volume of 15
L. (Embodiment 142) The antibody of any one of embodiments 132-141, wherein
the
antibody is injected at a concentration of about 0.1 pept to about 1.0 MIL.
(Embodiment
143) The antibody of any one of embodiments 132-142, wherein the size
exclusion
chromatography is performed on a Shimadzu UPLC instrument. (Embodiment 144)
The
antibody of any one of embodiments 132-143, wherein the size exclusion
chromatography is
performed at a flow rate of 0.2 mL/min. (Embodiment 145) The antibody of any
one of
embodiments 132-144, wherein the size exclusion chromatography is performed at
a column
oven temperature of 30 C. (Embodiment 146) The antibody of any one of
embodiments 132-
145, wherein the percentage of monomer is calculated using Shimadzu software.
(Embodiment 147) The antibody of any one of embodiments 132-146, wherein the
size
exclusion chromatography is performed as described in Example 2.
1002131 (Embodiment 148) The anti-TL1A antibody of any one of embodiments 1-
147,
wherein the anti-TL1A is expressed at a concentration of at least about 2
g/mL, between
about 2 mg/mL and about 60 g/mL, between about 5 mg/mL and about 60 g/mL,
between
about 10 [tg/mL and about 60 g/mL, at least about 5 g/mL, at least about 10
pg/mL, at
least about 15 ps/mL, at least about 20 ps/mL, between about 2 [tg/mL and
about 50 ps/mL,
between about 2 pg/mL and about 40 g/mL, between about 2 .g/mL and about 30
ps/mL,
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between about 2 ng/mL and about 20 ng/mL, between about 5 ng/mL and about 50
ttg/mL,
between about 5 ng/mL and about 40 ng/mL, between about 5 ng/mL and about 30
ttg/mL,
between about 10 ng/mL and about 50 ing/mL, between about 10 ng/mL and about
40
ttg/mL, or between about 10 ng/mL and about 30 ng/mL, as determined by a
method
disclosed herein. (Embodiment 149) The anti-TL1A antibody of any one of
embodiments 1-
147, wherein the expression level is at least about 2, 3, 4, 5, 6, 7, 8, 9,
10,11, 12,13, 14,15,
16, 17, 18, 19, 20, 21,22, 23,24, 25,26, 27,28, 29, or 30 ng/mL as determined
by a method
disclosed herein. (Embodiment 150) The antibody of embodiment 148 or
embodiment 149,
wherein the antibody is expressed in FreeStyle 293 -F cells. (Embodiment 151)
The antibody
of any one of embodiments 148-150, wherein the antibody is expressed as
described in
Example 2. (Embodiment 152) The antibody of any one of embodiments 148-151,
wherein
the antibody expression level is quantified using Enzyme-Linked Immunosorbent
assay
(ELISA). (Embodiment 153) The antibody of embodiment 152, wherein the ELISA
comprises coating a surface of a substrate with a capture antibody that binds
to a human or
humanized antibody, applying the anti-TL1A antibody to the substrate, and
applying to the
substrate a second antibody that binds to a human or humanized antibody.
(Embodiment 154)
The antibody of embodiment 153, where the capture antibody comprises an anti-
kappa
antibody. (Embodiment 155) The antibody of embodiment 153 or embodiment 154,
where
the second antibody comprises an anti-Fc antibody. (Embodiment 156) The
antibody of any
one of embodiments 152-155, where the ELISA is performed as described in
Example 2.
1002141 (Embodiment 157) A method of treating inflammatory bowel disease (MD)
in a
subject in need thereof, the method comprising administering to the subject an
antibody or
antigen binding fragment of any one of embodiments 1-156. (Embodiment 158) The
method
of embodiment 157, wherein the IBD comprises Crohn's Disease. (Embodiment 159)
The
method of embodiment 157, wherein the 1BD comprises ulcerative colitis.
1002151 (Embodiment 160) A nucleic acid encoding the antibody of any one of
embodiments 1-156. (Embodiment 161) A vector comprising the nucleic acid of
embodiment
160. (Embodiment 162) A cell comprising the nucleic acid of embodiment 160.
(Embodiment
163) A cell comprising the vector of embodiment 161.
1002161 Antibody Properties
1002171 Anti-TL1A antibodies described herein bind to specific regions or
epitopes of
human TL1A. In various embodiments, an anti-TL1A antibody provided herein has
a binding
affinity to human TL1A of less than about 1E-7, 1E-11, 1E-9, or 1E-1 Kd. In
some cases, the
binding affinity is from about 1E-9to about 1E-10 Kd. In some embodiments, an
anti-TL1A
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antibody provided herein has a binding affinity to murine TL1A and/or rat TL1A
of less than
about 1E-7, 1E-8, 1E-9, 1E-1 , or 1E-1-1- Kd. Methods for determining binding
affinity are
exemplified herein, including in Example 2.
1002181 In various embodiments, an anti-TL1A antibody provided herein is an
antagonist
of a TL1A receptor, such as, but not limited to, DR3 and TR6/DcR3. In certain
embodiments,
the antibody inhibits at least about 10%, at least about 20%, at least about
30%, at least about
50%, at least about 75%, at least about 90%, or about 100% of one or more
activity of the
bound TL1A receptor. In certain embodiments, the anti-TL1A antibody inhibits
TL1A
activation as measured by interferon gamma release in human blood. In certain
embodiments,
the antibody inhibits interferon gamma release in human blood at an IC50 of
between about 1
nanomolar and about 30 picomolar. In certain embodiments, the antibody
inhibits interferon
gamma release in human blood at an IC50 of between about 500 picomolar and
about 30
picomolar. In certain embodiments, the antibody inhibits interferon gamma
release in human
blood at an IC50 of between about 200 picomolar and about 30 picomolar. In
certain
embodiments, the antibody inhibits interferon gamma release in human blood at
an IC50 of
less than or equal to about 200 picomolar. In certain embodiments, the
antibody inhibits
interferon gamma release in human blood at an IC50 of less than or equal to
about 100
picomolar.
1002191 In various embodiments, an anti-TL1A antibody provided herein
comprises at
least about 80% monomeric fraction after expression and purification as
described in
Example 2 or elsewhere herein. In various embodiments, an anti-TL1A antibody
provided
herein comprises at least about 85% monomeric fraction after expression and
purification as
described in Example 2 or elsewhere herein. In various embodiments, an anti-
TL1A antibody
provided herein comprises at least about 90% monomeric fraction after
expression and
purification as described in Example 2 or elsewhere herein. In various
embodiments, an anti -
TL1A antibody provided herein comprises at least about 91%, 92%, 93%, 94%,
95%, 96%,
97%, 98%, 99%, or 100% monomeric fraction after expression and purification as
described
in Example 2 or elsewhere herein.
1002201 In various embodiments, an anti-TL1A antibody provided herein has at
least about
2 l.t.g/mL expression as determined by the method disclosed herein. In some
embodiments, the
anti-TL1A antibody has about 2 g/mL to about 60 [tg/mL expression as
determined by the
method disclosed herein. In some embodiments, the anti-TL1A antibody has about
5 ittg/mL
to about 60 [tg/mL expression as determined by the method disclosed herein. In
some
embodiments, the anti-TL1A antibody has about 10 pg/mL to about 60 [tg/mL
expression as
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determined by the method disclosed herein. In some embodiments, the anti-TL I
A antibody
has at least about 5 lig/mL expression as determined by the method disclosed
herein. In some
embodiments, the anti-TLI A antibody has at least about 10 vg/mL expression as
determined
by the method disclosed herein. In some embodiments, the anti-TLI A antibody
has at least
about 15 l.tg/mL expression as determined by the method disclosed herein. In
some
embodiments, the anti-TL1A antibody has at least about 20 ttg/mL expression as
determined
by the method disclosed herein. In some embodiments, the anti-TL I A antibody
expresses
between about 21.tg/mL and about 50 .g/mL, between about 2 t.t.g/mL and about
40 ttg/mL,
between about 2 [tg/mL and about 30 ug/mL expression, between about 2 ug/mL
and about
20 [tg/mL, between about 5 [tg/mL and about 50 [tg/mL, between about 5 [tg/mL
and about
40 l_tg/mL, between about 5 [tg/mL and about 30 l_ig/mL, between about 10
[tg/mL and about
50 p.g/mL, between about 10 l.tg/mL and about 40 lig/mL, or between about 10
l.tg/mL and
about 30 [tg/mL as determined by the method disclosed herein. In some
embodiments, the
anti-TLIA antibody has about 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,
16, 17, 18, 19, 20,
21, 22, 23, 24, 25, 26,27, 28,29, 30 [tg/mL expression as determined by the
method
disclosed herein. Methods disclosed herein include those described in Example
2.
[00221] In various embodiments, an anti-TLIA antibody provided herein is
humanized
and has less than about 20% non-human sequence in the framework region of each
of the
heavy chain and light chain variable regions. For instance, the humanized
antibody comprises
less than about 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%,
7%,
6%, 5%, 4%, 3%, 2%, or 1% non-human sequence in the framework region of each
of the
heavy chain and light chain variable regions. As another example, the
humanized antibody
comprises about or less than about 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4,
3, 2, or 1 non-human
sequences in the framework region of each of the heavy chain and light chain
variable
regions. The humanized heavy chain variable domain may comprise IGHV1-46*02
framework with no or fewer than about 10,9, 8, 7, 6, 5, 4, 3, 2, or 1 non-
human mutations.
The humanized light chain variable domain may comprise IGKV3 -20 framework
with no or
fewer than about 10,9, 8, 7, 6, 5, 4, 3, 2, or I non-human mutations.
[00222] Epitop e
1002231 Various embodiments provide for an anti-TLIA antibody that binds to
the same
region of a TLIA protein or portion thereof as a reference antibody such as
the anti-TL1A
antibodies described herein. In some embodiments, the reference antibody
comprises
antibody A, B, C, D, E, F, G, H, A2, B2, C2, D2, E2, F2, G2, or H2, or a
combination
thereof. In some embodiments, provided herein is an anti-TLI A antibody that
binds
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specifically to the same region of TL1A as a reference antib ody comprising a
heavy chain
sequence at least about 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%
identical
to SEQ ID NO: 104, and alight chain comprising a sequence at least about 90%,
92%, 93%,
94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 201. In some
embodiments, provided herein is an anti-TL1A antibody that binds specifically
to the same
region of TL1A as a reference antibody comprising a heavy chain sequence at
least about
90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO:
107,
and a light chain comprising a sequence at least about 90%, 92%, 93%, 94%,
95%, 96%,
97%, 98%, 99% or 100% identical to SEQ ID NO: 201.
1002241 Non-limiting methods for determining whether an anti-TL1A antibody
(i.e. test
antibody) binds to the same region of a TL1A protein or portion thereof as an
antibody
described herein are provided. An exemplary embodiment comprises a competition
assay.
For instance, the method comprises determining whether the test antibody can
compete with
binding between the reference antibody and the TL1A protein or portion
thereof, or
determining whether the reference antibody can compete with binding between
the test
antibody and the TL1A protein or portion thereof. Exemplary methods include
use of surface
plasmon resonance to evaluate whether an anti-TL1A antibody can compete with
the binding
between TL1A and another anti-TL1A antibody. In some cases, surface plasmon
resonance is
utilized in the competition assay. Non-limiting methods are described in the
examples.
[00225] In certain embodiments, disclosed herein are antibodies that compete
for binding
TL1A with the antibodies described herein. In certain embodiments, disclosed
herein are
antibodies that bind a discrete epitope that overlaps with an epitope of TL1A
bound by an
antibody described herein. In certain embodiments, disclosed herein are
antibodies that bind
the same epitope of TL1A, overlap with the an epitope of TL1A by one or more
amino acid
residues, or that compete for binding to an epitope of TL1A with an antibody
or fragment
thereof that comprises a heavy chain variable region comprising the amino acid
sequence of
SEQ ID NO: 104; and alight chain variable region comprising the amino acid of
SEQ ID
NO: 201. In certain embodiments, disclosed herein are antibodies that bind the
same epitope
of TL1A, overlap with the an epitope of TL1A by one or more amino acid
residues, or that
compete for binding to an epitope of TL with an antibody or fragment thereof
that
comprises a heavy chain variable region comprising the amino acid sequence of
SEQ ID NO:
107; and a light chain variable region comprising the amino acid of SEQ ID NO:
201.
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4.3 Assays
1002261 An exemplary screening paradigm for identification of antibody
variants that
express well in mammalian cells and preserve TL I A binding activity while
minimizing the
propensity of the antibody to aggregate comprises a five-step process. This
screen was
performed as detailed in the examples. Briefly, (1) variants were cloned and
transiently
expressed as intact Ig in 293 cells using small-scale (3 mL, 6-well culture
plates)
transfections, (2) the expression level of the antibody was assessed in the
culture supernatant
96-120 hours after transfection using an antibody quantitation ET,TSA, (3) the
binding of the
supernatant antibody variants to human TL1A was assessed by ELISA, (4) the
antibody was
purified in a single step using Protein A and (5) the material was analyzed by
analytical SEC
to assess monomer/aggregate content. This approach enabled identification of
variants that
expressed well, preserved binding to TL1A, and displayed high monomer content.
1002271 Further provided herein are methods for analyzing antibody solubility
based on
percentage of monomeric fraction. For example, as described in Example 2.
1002281 Further provided herein are assays for quantifying antibody
expression. For
example, as described in Example 2.
1002291 Further provided herein are assays for quantifying immunogenicity of
an
antibody.
1002301 The antibodies described herein can be assayed for specific binding by
any
method known in the art. The immunoassays which can be used include, but are
not limited
to, competitive and non-competitive assay systems using techniques such as
BIAcore
analysis, FACS analysis, immunofluorescence, immunocytochemistry, Western
blots,
radioimmunoassays, ELISA, "sandwich" immunoassays, immunoprecipitation assays,
precipitation reactions, gel diffusion precipitin reactions, immunodiffusion
assays,
agglutination assays, complement-fixation assays, immunoradiometric assays,
fluorescent
immunoassays, and protein A immunoassays. Such assays are provided in for
e.g., Ausubel et
al., eds, 1994, Current Protocols in Molecular Biology, Vol. 1, John Wiley &
Sons, Inc., New
York.
4.4 Methods of Generating Antibodies
1002311 In various embodiments, monoclonal antibodies are prepared using
methods
known in the art, such as, but not limited to the hybridoma method, where a
host animal is
immunized to elicit the production by lymphocytes of antibodies that will
specifically bind to
an immunizing antigen (Kohler and Milstein (1975) Nature 256:495). Hybridomas
produce
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monoclonal antibodies directed specifically against a chosen antigen. The
monoclonal
antibodies are purified from the culture medium or ascites fluid by techniques
known in the
art, when propagated either in vitro or in vivo.
1002321 In some embodiments, monoclonal antibodies are made using recombinant
DNA
methods. The polynucleotides encoding a monoclonal antibody are isolated from
mature B-
cells or hybridoma cells. The isolated polynucleotides encoding the heavy and
light chains
are then cloned into suitable expression vectors, which when transfected into
host cells (e.g.,
E. coil cells, simian COS cells, Chinese hamster ovary (CHO) cells, or myeloma
cells)
generate monoclonal antibodies. The polynucleotide(s) encoding a monoclonal
antibody can
further be modified in a number of different manners using recombinant DNA
technology to
generate alternative antibodies.
1002331 In various embodiments, a chimeric antibody, a molecule in which
different
portions are derived from different animal species, such as those having a
variable region
derived from a murine monoclonal antibody and a human immunoglobulin constant
region
(e.g., humanized antibodies) can be generated.
1002341 In some embodiments, the anti-TL1 A monoclonal antibody is a humanized
antibody, to reduce antigenicity and HAMA (human anti-mouse antibody)
responses when
administered to a human subject. Humanized antibodies can be produced using
various
techniques known in the art. For example, an antibody is humanized by (1)
determining the
nucleotide and predicted amino acid sequence of the starting antibody light
and heavy
variable domains; (2) designing the humanized antibody, e.g., deciding which
antibody
framework region to use during the humanizing process; (3) the actual
humanizing
methodologies/techniques; and (4) the transfection and expression of the
humanized
antibody. In various embodiments, a humanized antibody can be further
optimized to
decrease potential immunogenicity, while maintaining functional activity, for
therapy in
humans.
1002351 Humanized antibodies can also be made in transgenic mice containing
human
immunoglobulin loci that are capable, upon immunization, of producing the full
repertoire of
human antibodies in the absence of endogenous immunoglobulin production. A
humanized
antibody may also be obtained by a genetic engineering approach that enables
production of
affinity-matured human-like polyclonal antibodies in large animals.
1002361 A fully humanized antibody may be created by first designing a
variable region
amino acid sequence that contains non-human, e.g., rodent-derived CDRs,
embedded in
human-derived framework sequences. The non-human CDRs provide the desired
specificity.
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Accordingly, in some cases these residues are included in the design of the
reshaped variable
region essentially unchanged. In some cases, modifications should therefore be
restricted to a
minimum and closely watched for changes in the specificity and affinity of the
antibody. On
the other hand, framework residues in theory can be derived from any human
variable region.
A human framework sequences should be chosen, which is equally suitable for
creating a
reshaped variable region and for retaining antibody affinity, in order to
create a reshaped
antibody which shows an acceptable or an even improved affinity. The human
framework
may be of germline origin, or may be derived from non -germline (e.g., mutated
or affinity
matured) sequences. Genetic engineering techniques well known to those in the
art, for
example, but not limited to, phage display of libraries of human antibodies,
transgenic mice,
human-human hybridoma, hybrid hybridoma, B cell immortalization and cloning,
single-cell
RT¨PCR or HuRAb Technology, may be used to generate a humanized antibody with
a
hybrid DNA sequence containing a human framework and a non-human CDR.
1002371 In certain embodiments, the anti-TL1A antibody is a human antibody.
Human
antibodies can be directly prepared using various techniques known in the art.
Immortalized
human B lymphocytes immunized in vitro or isolated from an immunized in divi
dual that
produce an antibody directed against a target antigen can be generated.
1002381
Chimeric, humanized and human antibodies may be produced by recombinant
expression. Recombinant polynucleotide constructs typically include an
expression control
sequence operably linked to the coding sequences of antibody chains, including
naturally
associated or heterologous promoter regions. In certain embodiments, it may be
desirable to
generate amino acid sequence variants of these humanized antibodies,
particularly where
these improve the binding affinity or other biological properties of the
antibody.
1002391 In certain embodiments, an antibody fragment is used to treat and/or
ameliorate
lBD. Various techniques are known for the production of antibody fragments.
Generally,
these fragments are derived via proteolytic digestion of intact antibodies
(for example
Morimoto et al., 1993, Journal of Biochemical and Biophysical Methods 24:107-
117;
Brennan et al., 1985, Science, 229:81). Fab, Fv, and scFv antibody fragments
can all be
expressed in and secreted from E. coli or other host cells, thus allowing the
production of
large amounts of these fragments. Other techniques for the production of
antibody fragments
will be apparent to the skilled practitioner.
1002401 According to the present disclosure, techniques can be adapted for the
production
of single-chain antibodies specific to TL1A. In addition, methods can be
adapted for the
construction of Fab expression libraries to allow rapid and effective
identification of
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monoclonal Fab fragments with the desired specificity for TL1A, or
derivatives, fragments,
analogs or homologs thereof. Antibody fragments may be produced by techniques
in the art
including, but not limited to: (a) a F(ab')2 fragment produced by pepsin
digestion of an
antibody molecule; (b) a Fab fragment generated by reducing the disulfide
bridges of an
F(ab')2 fragment, (c) a Fab fragment generated by the treatment of the
antibody molecule
with papain and a reducing agent, and (d) Fv fragments.
1002411 Also provided herein are modified antibodies comprising any type of
variable
region that provides for the association of the antibody with TL1A. Those
skilled in the art
will appreciate that the modified antibodies may comprise antibodies (e.g.,
full-length
antibodies or immunoreactive fragments thereof) in which at least a fraction
of one or more
of the constant region domains has been deleted or otherwise altered so as to
provide desired
biochemical characteristics such as decreasing TL1A. In certain embodiments,
the variable
regions in both the heavy and light chains are altered by at least partial
replacement of one or
more CDRs and, if necessary, by partial framework region replacement and
sequence
changing. In some embodiments, the replaced CDRs may be derived from an
antibody of the
same class, subclass, from an antibody of a different class, for instance,
from an antibody
from a different species and/or a combination thereof. In some embodiments,
the constant
region of the modified antibodies will comprise a human constant region.
Modifications to
the constant region compatible with this disclosure comprise additions,
deletions or
substitutions of one or more amino acids in one or more domains.
1002421 In various embodiments, the expression of an antibody or antigen-
binding
fragment thereof as described herein can occur in either prokaryotic or
eukaryotic cells.
Suitable hosts include bacterial or eukaryotic hosts, including yeast,
insects, fungi, bird and
mammalian cells either in vivo, or in situ, or host cells of mammalian,
insect, bird or yeast
origin. The mammalian cell or tissue can be of human, primate, hamster,
rabbit, rodent, cow,
pig, sheep, horse, goat, dog or cat origin, but any other mammalian cell may
be used. In other
embodiments, the antibody or antigen-fragment thereof as described herein may
be
transfected into the host.
1002431 In some embodiments, the expression vectors are transfected into the
recipient cell
line for the production of the chimeric, humanized, or composite human
antibodies described
herein. In various embodiments, mammalian cells can be useful as hosts for the
production of
antibody proteins, which can include, but are not limited to cells of
fibroblast origin, such as
Vero (ATCC CRL 81) or CHO-Kt (ATCC CRL 61) cells, HeLa cells and L cells.
Exemplary
eukaryotic cells that can be used to express polypeptides include, but are not
limited to, COS
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cells, including COS 7 cells; 293 cells, including 293-6E cells; CHO cells,
including CHO¨
S and DG44 cells; PER.C6Tm cells (Crucell); and NSO cells. In some
embodiments, a
particular eukaryotic host cell is selected based on its ability to make
desired post-
translational modifications to the heavy chains and/or light chains.
[00244] A number of suitable host cell lines capable of secreting intact
heterologous
proteins have been developed in the art, and include, but are not limited to
CHO cell lines,
various COS cell lines, HeLa cells, L cells and multiple myeloma cell lines.
[00245] An expression vector carrying a chimeric, humanized, or composite
human
antibody construct, antibody or antigen-binding fragment thereof as described
herein can be
introduced into an appropriate host cell by any of a variety of suitable
means, depending on
the type of cellular host including, but not limited to transformation,
transfection, lipofection,
conjugation, electroporation, direct microinjection, and microprojectile
bombardment, as
known to one of ordinary skill in the art. Expression vectors for these cells
can include
expression control sequences, such as an origin of replication sites, a
promoter, an enhancer
and necessary processing information sites, such as ribosome binding sites,
RNA splice sites,
polyadenylation sites, and transcriptional terminator sequences.
[00246] In various embodiments, yeast can also be utilized as hosts for the
production of
the antibody molecules or peptides described herein. In various other
embodiments, bacterial
strains can also be utilized as hosts for the production of the antibody
molecules or peptides
described herein. Examples of bacterial strains include, but are not limited
to E. coil, Bacillus
species, enterobacteria, and various Pseudomonas species.
[00247] In some embodiments, one or more antibodies or antigen-binding
fragments
thereof as described herein can be produced in vivo in an animal that has been
engineered
(transgenic) or transfected with one or more nucleic acid molecules encoding
the
polypeptides, according to any suitable method. For production of transgenic
animals,
transgenes can be microinjected into fertilized oocytes, or can be
incorporated into the
genome of embryonic stem cells, and the nuclei of such cells transferred into
enudeated
oocytes. Once expressed, antibodies can be purified according to standard
procedures of the
art, including HPLC purification, column chromatography, gel electrophoresis
and the like
(see generally, Scopes, Protein Purification (Springer-Verlag, NY, 1982)).
[00248] Once expressed in the host, the whole antibodies, antibody-
fragments (e.g.,
individual light and heavy chains), or other immunoglobulin forms of the
present disclosure
can be recovered and purified by known techniques, e.g., immunoabsorption or
immunoaffinity chromatography, chromatographic methods such as HPLC (high
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performance liquid chromatography), ammonium sulfate precipitation, gel
electrophoresis, or
any combination of these. See generally, Scopes, PROTEIN PURIF. (Springer-
Verlag, NY,
1982). Substantially pure immunoglobulins of at least about 90% to 95%
homogeneity are
advantageous, as are those with 98% to 99% or more homogeneity, particularly
for
pharmaceutical uses. Once purified, partially or to homogeneity as desired, a
humanized or
composite human antibody can then be used therapeutically or in developing and
performing
assay procedures, immunofluorescent stainings, etc. See generally, Vols. I &
II Immunol.
Meth. (Lefkovits & Pernis, eds., Acad. Press, NY, 1979 and 1981).
[00249] Various embodiments provide for a genetic construct comprising a
nucleic acid
encoding an anti-TL I A antibody or fragment provided herein. Genetic
constructs of the
antibody can be in the form of expression cassettes, which can be suitable for
expression of
the encoded anti-TL1A antibody or fragment. The genetic construct may be
introduced into a
host cell with or without being incorporated in a vector. For example, the
genetic construct
can be incorporated within a liposome or a virus particle. Alternatively, a
purified nucleic
acid molecule can be inserted directly into a host cell by methods known in
the art. The
genetic construct can be introduced directly into cells of a host subject by
transfection,
infection, electroporation, cell fusion, protoplast fusion, microinjection or
ballistic
bombardment.
[00250] Various embodiments provide a recombinant vector comprising the
genetic
construct of an antibody provided herein. The recombinant vector can be a
plasmid, cosmid
or phage. The recombinant vectors can include other functional elements; for
example, a
suitable promoter to initiate gene expression.
[00251] Various embodiments provide a host cell comprising a genetic construct
and/or
recombinant vector described herein.
[00252] Various host systems are also advantageously employed to express
recombinant
protein. Examples of suitable mammalian host cell lines include the COS-7
lines of monkey
kidney cells, and other cell lines capable of expressing an appropriate vector
including, for
example, L cells, C127, 3 T3, Chinese hamster ovary (CHO), HeLa and BHK cell
lines.
Mammalian expression vectors can comprise non-transcribed elements such as an
origin of
replication, a suitable promoter and enhancer linked to the gene to be
expressed, and other 5'
or 3' flanking non-transcribed sequences, and 5' or 3' non-translated
sequences, such as
necessary ribosome binding sites, a polyadenylation site, splice donor and
acceptor sites, and
transcriptional termination sequences.
[00253] The proteins produced by a transformed host can be purified according
to any
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suitable method. Such standard methods include chromatography (e.g., ion
exchange, affinity
and sizing column chromatography), centrifugation, differential solubility, or
by any other
standard technique for protein purification. Affinity tags such as
hexahistidine (SEQ ID NO:
391), maltose binding domain, influenza coat sequence and glutathione-S-
transferase can be
attached to the protein to allow easy purification by passage over an
appropriate affinity
column. Isolated proteins can also be physically characterized using such
techniques as
proteolysis, nuclear magnetic resonance and x-ray crystallography. Recombinant
protein
produced in bacterial culture can be isolated.
1002541 One of skill will recognize that individual substitutions,
deletions or additions to a
nucleic acid, peptide, polypeptide, or protein sequence which alters a single
amino acid or a
small percentage of amino acids in the encoded sequence is a "conservatively
modified
variant" where the alteration results in the substitution of an amino acid
with a chemically
similar amino acid and retain the ability to specifically bind the target
antigen. Such
conservatively modified variants are in addition to and do not exclude
polymorphic variants,
interspecies homologs, and alleles consistent with the disclosure.
1002551 A given amino acid can be replaced by a residue having
similar physiochemical
characteristics, e.g., substituting one aliphatic residue for another (such as
He, Val, Leu, or
Ala for one another), or substitution of one polar residue for another (such
as between Lys
and Arg; Glu and Asp; or Gln and Asn). Other such conservative substitutions,
e.g.,
substitutions of entire regions having similar hydrophobicity characteristics,
are well known.
Polypeptides comprising conservative amino acid substitutions can be tested in
any one of the
assays described herein to confirm that a desired activity, e.g. antigen-
binding activity and
specificity of a native or reference polypeptide is retained.
1002561 Particular conservative substitutions include, for example;
Ala into Gly or into
Ser; Arg into Lys; Asn into Gin or into H is; Asp into Glu; Cy s into Ser; Gin
into Asn; Glu
into Asp; Gly into Ala or into Pro; His into Asn or into Gin; lie into Leu or
into Val; Leu into
lie or into Val; Lys into Arg, into Gin or into Glu; Met into Leu, into Tyr or
into lie; Phe into
Met, into Leu or into Tyr; Ser into Thr; Thr into Ser; Trp into Tyr; Tyr into
Trp; and/or Phe
into Val, into lie or into Leu.
1002571 In some embodiments, the antibody and/or antigen-binding fragment
thereof
described herein can be a variant of a sequence described herein, e.g., a
conservative
substitution variant of an antibody polypeptide. In some embodiments, the
variant is a
conservatively modified variant. A variant may refer to a polypeptide
substantially
homologous to a native or reference polypeptide, but which has an amino acid
sequence
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different from that of the native or reference polypeptide because of one or a
plurality of
deletions, insertions or substitutions. Variant polypeptide-encoding DNA
sequences
encompass sequences that comprise one or more additions, deletions, or
substitutions of
nucleotides when compared to a native or reference DNA sequence, but that
encode a variant
protein or fragment thereof that retains activity, e.g., antigen-specific
binding activity for the
relevant target polypeptide.
[00258] Alterations of the native amino acid sequence can be accomplished by
any of a
number of techniques known to one of skill in the art. Mutations can be
introduced at
particular loci or by oligonucleotide-directed site-specific mutagenesis
procedures.
Techniques for making such alterations are very well established and include,
for example,
those disclosed by Walder et al. (Gene 42: 133, 1986); Bauer et al. (Gene
37:73, 1985); Craik
(BioTechniques, January 1985, 12-19); Smith et al. (Genetic Engineering:
Principles and
Methods, Plenum Press, 1981).
[00259] Nucleic acid molecules encoding amino acid sequence variants of
antibodies are
prepared by a variety of methods known in the art. These methods include, but
are not limited
to, preparation by oligonucleotide-mediated (or site-directed) mutagenesis,
PCR mutagenesis,
and cassette mutagenesis of an earlier prepared variant or a non-variant
version of the
antibody. A nucleic acid sequence encoding at least one antibody, portion or
polypeptide as
described herein can be recombined with vector DNA in accordance with
conventional
techniques, including but not limited to, blunt-ended or staggered-ended
termini for ligation
and restriction enzyme digestion. Techniques for such manipulations are
disclosed, e.g., by
Maniatis et al., Molecular Cloning, Lab. Manual (Cold Spring Harbor Lab.
Press, NY, 1982
and 1989), and can be used to construct nucleic acid sequences which encode a
monoclonal
antibody molecule or antigen-binding region.
[00260] In some embodiments, a nucleic acid encoding an antibody or antigen-
binding
fragment thereof as described herein is comprised by a vector. In some of the
aspects
described herein, a nucleic acid sequence encoding an antibody or antigen-
binding fragment
thereof as described herein, or any module thereof, is operably linked to a
vector. The term
"vector," as used herein, refers to a nucleic acid construct designed for
delivery to a host cell
or for transfer between different host cells. As used herein, a vector can be
viral or non-viral.
The term "vector" encompasses any genetic element that is capable of
replication when
associated with the proper control elements and that can transfer gene
sequences to cells. A
vector can include, but is not limited to, a cloning vector, an expression
vector, a plasmid,
phage, transposon, cosmid, chromosome, virus, virion, etc.
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1002611 As used herein, the term "expression vector" refers to a vector that
directs
expression of an RNA or polypeptide from sequences linked to transcriptional
regulatory
sequences on the vector. The term "expression" refers to the cellular
processes involved in
producing RNA and proteins and as appropriate, secreting proteins, including
where
applicable, but not limited to, for example, transcription, transcript
processing, translation and
protein folding, modification and processing. "Expression products" include
RNA transcribed
from a gene, and polypeptides obtained by translation of mRNA transcribed from
a gene. The
term "gene" means the nucleic acid sequence which is transcribed (DNA) to RNA
in vitro or
in vivo when operably linked to appropriate regulatory sequences. The gene may
or may not
include regions preceding and following the coding region, e.g., 5'
untranslated (5 'UTR) or
"leader" sequences and 3' UTR or "trailer" sequences, as well as intervening
sequences
(introns) between individual coding segments (exons).
1002621 As used herein, the term "viral vector" refers to a nucleic
acid vector construct
that includes at least one element of viral origin and has the capacity to be
packaged into a
viral vector particle. The viral vector can contain the nucleic acid encoding
an antibody or
antigen-binding portion thereof as described herein in place of non-essential
viral genes. The
vector and/or particle may be utilized for the purpose of transferring any
nucleic acids into
cells either in vitro or in vivo. Numerous forms of viral vectors are known in
the art.
1002631 By "recombinant vector," it is meant that the vector includes a
heterologous
nucleic acid sequence, or "transgene" that is capable of expression in vivo.
4.5 Pharmaceutical Compositions
1002641 In one aspect, anti-TL1A antibodies provided herein are formulated
into
pharmaceutical compositions that are useful in a variety of applications
including, but not
limited to, therapeutic methods, such as the treatment of 1BD. The methods of
use may be in
vitro, ex vivo, or in vivo methods. In certain embodiments, the disease
treated with anti-TL1A
antibody is IBD, CD, UC and/or MR-UC.
1002651 In various embodiments, the pharmaceutical compositions are formulated
for
delivery via any route of administration. "Route of administration" includes
any
administration pathway known in the art, including but not limited to
intravenous,
subcutaneous, aerosol, nasal, oral, transmucosal, transdermal and parenteral.
In example
embodiments, the route of administration is subcutaneous.
1002661 The pharmaceutical compositions may contain any pharmaceutically
acceptable
carrier. "Pharmaceutically acceptable carrier" refers to a pharmaceutically
acceptable
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material, composition, or vehicle that is involved in carrying or transporting
a compound of
interest from one tissue, organ, or portion of the body to another tissue,
organ, or portion of
the body. For example, the carrier may be a liquid or solid filler, diluent,
excipient, solvent,
or encapsulating material, or a combination thereof. Each component of the
carrier must be
"pharmaceutically acceptable" in that it must be compatible with the other
ingredients of the
formulation. It must also be suitable for use in contact with any tissues or
organs with which
it may come in contact, meaning that does not carry a risk of toxicity,
irritation, allergic
response, immunogenicity, or any other complication that excessively outweighs
its
therapeutic benefits.
1002671 In various embodiments, provided are pharmaceutical compositions
including a
pharmaceutically acceptable excipient along with a therapeutically effective
amount of an
anti-TL1A antibody. "Pharmaceutically acceptable excipient" means an excipient
that is
useful in preparing a pharmaceutical composition that is generally safe, non-
toxic, and
desirable, and includes excipients that are acceptable for veterinary use as
well as for human
pharmaceutical use. The active ingredient can be mixed with excipients which
are
pharmaceutically acceptable and compatible with the active ingredient and in
amounts
suitable for use in therapeutic methods described herein. Such excipients may
be solid, liquid,
semisolid, or, in the case of an aerosol composition, gaseous. Suitable
excipients may be
selected for different routes of administration (e.g., subcutaneous,
intravenous, oral). Non-
limiting examples include, for example, starch, glucose, lactose, sucrose,
gelatin, malt, rice,
flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium
chloride, dried
skim milk, water, saline, dextrose, propylene glycol, glycerol, ethanol,
mannitol, poly sorb ate
or the like and combinations thereof. In addition, if desired, the composition
can contain
auxiliary substances such as wetting or emulsifying agents, pH buffering
agents and the like
which enhance or maintain the effectiveness of the active ingredient.
Therapeutic
compositions as described herein can include pharmaceutically acceptable
salts.
Pharmaceutically acceptable salts include the acid addition salts formed with
inorganic acids
such as, for example, hydrochloric or phosphoric acids, organic acids, for
example, acetic,
tartaric or mandelic, salts formed from inorganic bases such as, for example,
sodium,
potassium, ammonium, calcium or ferric hydroxides, and salts formed from
organic bases
such as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine,
procaine and the
like. Liquid compositions can contain liquid phases in addition to and in the
exclusion of
water, for example, glycerin, vegetable oils such as cottonseed oil, and water-
oil emulsions.
Physiologically tolerable carriers are well known in the art. The amount of
antibody used that
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will be effective in the treatment of a particular disorder or condition will
depend on the
nature of the disorder or condition and can be determined by one of skill in
the art with
standard clinical techniques.
1002681 Non-limiting example compositions
1002691 In certain embodiments, provided herein are pharmaceutical
compositions
comprising an anti-TL1A antibody formulated for intravenous administration.
1002701 In certain embodiments, provided herein are pharmaceutical
compositions
comprising an anti-TL1A antibody formulated for subcutaneous administration.
1002711 In certain embodiments, provided herein are pharmaceutical
compositions
comprising an anti-TL1A antibody at a concentration of about or greater than
about 150
mg/mL. In some embodiments, the concentration is up to about 300 mg/mL. In
some
embodiments, the concentration is about or greater than about 155, 160, 165,
170, 175, 180,
185, 190, 195, or 200 mg/mL. In some embodiments, the concentration is about
150 mg/mL
to about 300 mg/mL, about 150 mg/mL to about 250 mg/mL, about 150 mg/mL to
about 225
mg/mL, about 150 mg/mL to about 220 mg/mL, about 150 mg/mL to about 210 mg/mL,
about 150 mg/mL to about 200 mg/mL, about 150 mg/mL to about 190 mg/mL, about
150
mg/mL to about 180 mg/mL, about 160 mg/mL to about 300 mg/mL, about 160 mg/mL
to
about 250 mg/mL, about 160 mg/mL to about 225 mg/mL, about 160 mg/mL to about
220
mg/mL, about 160 mg/mL to about 210 mg/mL, about 160 mg/mL to about 200 mg/mL,
about 160 mg/mL to about 190 mg/mL, about 160 mg/mL to about 180 mg/mL, about
170
mg/mL to about 300 mg/mL, about 170 mg/mL to about 250 mg/mL, about 170 mg/mL
to
about 225 mg/mL, about 170 mg/mL to about 220 mg/mL, about 170 mg/mL to about
210
mg/mL, about 170 mg/mL to about 200 mg/mL, about 170 mg/mL to about 190 mg/mL,
or
about 170 mg/mL to about 180 mg/mL. In some embodiments, about 150 mg to about
1,000
mg of the anti-TL1A antibody is present in the composition. For instance,
about 150 mg to
about 2000 mg, about 150 mg to about 1750 mg, about 150 mg to about 1500 mg,
about 150
mg to about 1250 mg, about 150 mg to about 1000 mg, about 150 mg to about 750
mg, about
150 to about 500 mg, about 150 to about 300 mg, about 150 to about 200 mg, or
about 150,
155, 160, 165,170,175,180,185, 190, 195,200,205,210,215,220,225 mg, 230, 235,
240,
245, 250, 255,260,265,270,275, 280, 285, 290,295,300,350,400,450,500, 550,
600,
650, 700, 750, 800, 850, 900,950, 1000, 1100, 1200, 1300,1400, 1500,1600,
1700,1800,
1900, or 2000 mg of the anti-TL1A antibody can be present in the composition.
1002721 Additionally, in some embodiments of the composition provided herein,
the
composition comprises an anti-TL1A antibody at a concentration greater than
about 50
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mg/mL. In some embodiments, the composition comprising an anti-TL1A antibody
at a
concentration greater than about 55 mg/mL, greater than about 60 mg/mL,
greater than about
65 mg/mL, greater than about 70 mg/mL, greater than about 75 mg/mL, greater
than about 80
mg/mL, greater than about 85 mg/mL, greater than about 90 mg/mL, greater than
about 95
mg/mL, greater than about 100 mg/mL, greater than about 105 mg/mL, greater
than about
110 mg/mL, greater than about 115 mg/mL, greater than about 120 mg/mL, greater
than
about 125 mg/mL, greater than about 130 mg/mL, greater than about 135 mg/mL,
greater
than about 140 mg/mL, or greater than about 145 mg/mL. In some embodiments,
the
composition comprising an anti-TL1A antibody at a concentration of about 55
mg/mL, about
60 mg/mL, about 65 mg/mL, about 70 mg/mL, about 75 mg/mL, about 80 mg/mL,
about 85
mg/mL, about 90 mg/mL, about 95 mg/mL, about 100 mg/mL, about 105 mg/mL, about
110
mg/mL, about 115 mg/mL, about 120 mg/mL, about 125 mg/mL, about 130 mg/mL,
about
135 mg/mL, about 140 mg/mL, or about 145 mg/mL. In some embodiments, the
composition
comprising an anti-TL1A antibody at a concentration of about 50 mg/mL to about
250
mg/mL, about 55 mg/mL to about 250 mg/mL, about 60 mg/mL to about 250 mg/mL,
about
65 mg/mL to about 250 mg/mL, about 70 mg/mL to about 250 mg/mL, about 75 mg/mL
to
about 250 mg/mL, about 80 mg/mL to about 250 mg/mL, about 85 mg/mL to about
250
mg/mL, about 90 mg/mL to about 250 mg/mL, about 95 mg/mL to about 250 mg/mL,
about
100 mg/mL to about 250 mg/mL, about 105 mg/mL to about 250 mg/mL, about 110
mg/mL
to about 250 mg/mL, about 115 mg/mL to about 250 mg/mL, about 120 mg/mL to
about 250
mg/mL, about 125 mg/mL to about 250 mg/mL, about 130 mg/mL to about 250 mg/mL,
about 135 mg/mL to about 250 mg/mL, about 140 mg/mL to about 250 mg/mL, about
145
mg/mL to about 250 mg/mL, about 150 mg/mL to about 250 mg/mL, about 155 mg/mL
to
about 250 mg/mL, about 160 mg/mL to about 250 mg/mL, about 165 mg/mL to about
250
mg/mL, about 170 mg/mL to about 250 mg/mL, about 175 mg/mL to about 250 mg/mL,
about 180 mg/mL to about 250 mg/mL, about 185 mg/mL to about 250 mg/mL, about
190
mg/mL to about 250 mg/mL, about 195 mg/mL to about 250 mg/mL, about 200 mg/mL
to
about 250 mg/mL, about 205 mg/mL to about 250 mg/mL, about 210 mg/mL to about
250
mg/mL, about 215 mg/mL to about 250 mg/mL, about 220 mg/mL to about 250 mg/mL,
about 225 mg/mL to about 250 mg/mL, about 230 mg/mL to about 250 mg/mL, about
235
mg/mL to about 250 mg/mL, about 240 mg/mL to about 250 mg/mL, about 245 mg/mL
to
about 250 mg/mL, about 50 mg/mL to about 240 mg/mL, about 55 mg/mL to about
240
mg/mL, about 60 mg/mL to about 240 mg/mL, about 65 mg/mL to about 240 mg/mL,
about
70 mg/mL to about 240 mg/mL, about 75 mg/mL to about 240 mg/mL, about 80 mg/mL
to
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about 240 mg/mL, about 85 mg/mL to about 240 mg/mL, about 90 mg/mL to about
240
mg/mL, about 95 mg/mL to about 240 mg/mL, about 100 mg/mL to about 240 mg/mL,
about
105 mg/mL to about 240 mg/mL, about 110 mg/mL to about 240 mg/mL, about 115
mg/mL
to about 240 mg/mL, about 120 mg/mL to about 240 mg/mL, about 125 mg/mL to
about 240
mg/mL, about 130 mg/mL to about 240 mg/mL, about 135 mg/mL to about 240 mg/mL,
about 140 mg/mL to about 240 mg/mL, about 145 mg/mL to about 240 mg/mL, about
150
mg/mL to about 240 mg/mL, about 155 mg/mL to about 240 mg/mL, about 160 mg/mL
to
about 240 mg/mL, about 165 mg/mL to about 240 mg/mL, about 170 mg/mL to about
240
mg/mL, about 175 mg/mL to about 240 mg/mL, about 180 mg/mL to about 240 mg/mL,
about 185 mg/mL to about 240 mg/mL, about 190 mg/mL to about 240 mg/mL, about
195
mg/mL to about 240 mg/mL, about 200 mg/mL to about 240 mg/mL, about 205 mg/mL
to
about 240 mg/mL, about 210 mg/mL to about 240 mg/mL, about 215 mg/mL to about
240
mg/mL, about 220 mg/mL to about 240 mg/mL, about 225 mg/mL to about 240 mg/mL,
about 230 mg/mL to about 240 mg/mL, about 235 mg/mL to about 240 mg/mL, about
50
mg/mL to about 230 mg/mL, about 55 mg/mL to about 230 mg/mL, about 60 mg/mL to
about 230 mg/mL, about 65 mg/mL to about 230 mg/mL, about 70 mg/mL to about
230
mg/mL, about 75 mg/mL to about 230 mg/mL, about 80 mg/mL to about 230 mg/mL,
about
85 mg/mL to about 230 mg/mL, about 90 mg/mL to about 230 mg/mL, about 95 mg/mL
to
about 230 mg/mL, about 100 mg/mL to about 230 mg/mL, about 105 mg/mL to about
230
mg/mL, about 110 mg/mL to about 230 mg/mL, about 115 mg/mL to about 230 mg/mL,
about 120 mg/mL to about 230 mg/mL, about 125 mg/mL to about 230 mg/mL, about
130
mg/mL to about 230 mg/mL, about 135 mg/mL to about 230 mg/mL, about 140 mg/mL
to
about 230 mg/mL, about 145 mg/mL to about 230 mg/mL, about 150 mg/mL to about
230
mg/mL, about 155 mg/mL to about 230 mg/mL, about 160 mg/mL to about 230 mg/mL,
about 165 mg/mL to about 230 mg/mL, about 170 mg/mL to about 230 mg/mL, about
175
mg/mL to about 230 mg/mL, about 180 mg/mL to about 230 mg/mL, about 185 mg/mL
to
about 230 mg/mL, about 190 mg/mL to about 230 mg/mL, about 195 mg/mL to about
230
mg/mL, about 200 mg/mL to about 230 mg/mL, about 205 mg/mL to about 230 mg/mL,
about 210 mg/mL to about 230 mg/mL, about 215 mg/mL to about 230 mg/mL, about
220
mg/mL to about 230 mg/mL, about 225 mg/mL to about 230 mg/mL, about 50 mg/mL
to
about 220 mg/mL, about 55 mg/mL to about 220 mg/mL, about 60 mg/mL to about
220
mg/mL, about 65 mg/mL to about 220 mg/mL, about 70 mg/mL to about 220 mg/mL,
about
75 mg/mL to about 220 mg/mL, about 80 mg/mL to about 220 mg/mL, about 85 mg/mL
to
about 220 mg/mL, about 90 mg/mL to about 220 mg/mL, about 95 mg/mL to about
220
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mg/mL, about 100 mg/mL to about 220 mg/mL, about 105 mg/mL to about 220 mg/mL,
about 110 mg/mL to about 220 mg/mL, about 115 mg/mL to about 220 mg/mL, about
120
mg/mL to about 220 mg/mL, about 125 mg/mL to about 220 mg/mL, about 130 mg/mL
to
about 220 mg/mL, about 135 mg/mL to about 220 mg/mL, about 140 mg/mL to about
220
mg/mL, about 145 mg/mL to about 220 mg/mL, about 150 mg/mL to about 220 mg/mL,
about 155 mg/mL to about 220 mg/mL, about 160 mg/mL to about 220 mg/mL, about
165
mg/mL to about 220 mg/mL, about 170 mg/mL to about 220 mg/mL, about 175 mg/mL
to
about 220 mg/mL, about 180 mg/mL to about 220 mg/mL, about 185 mg/mL to about
220
mg/mL, about 190 mg/mL to about 220 mg/mL, about 195 mg/mL to about 220 mg/mL,
about 200 mg/mL to about 220 mg/mL, about 205 mg/mL to about 220 mg/mL, about
210
mg/mL to about 220 mg/mL, about 215 mg/mL to about 220 mg/mL, about 50 mg/mL
to
about 210 mg/mL, about 55 mg/mL to about 210 mg/mL, about 60 mg/mL to about
210
mg/mL, about 65 mg/mL to about 210 mg/mL, about 70 mg/mL to about 210 mg/mL,
about
75 mg/mL to about 210 mg/mL, about 80 mg/mL to about 210 mg/mL, about 85 mg/mL
to
about 210 mg/mL, about 90 mg/mL to about 210 mg/mL, about 95 mg/mL to about
210
mg/mL, about 100 mg/mL to about 210 mg/mL, about 105 mg/mL to about 210 mg/mL,
about 110 mg/mL to about 210 mg/mL, about 115 mg/mL to about 210 mg/mL, about
120
mg/mL to about 210 mg/mL, about 125 mg/mL to about 210 mg/mL, about 130 mg/mL
to
about 210 mg/mL, about 135 mg/mL to about 210 mg/mL, about 140 mg/mL to about
210
mg/mL, about 145 mg/mL to about 210 mg/mL, about 150 mg/mL to about 210 mg/mL,
about 155 mg/mL to about 210 mg/mL, about 160 mg/mL to about 210 mg/mL, about
165
mg/mL to about 210 mg/mL, about 170 mg/mL to about 210 mg/mL, about 175 mg/mL
to
about 210 mg/mL, about 180 mg/mL to about 210 mg/mL, about 185 mg/mL to about
210
mg/mL, about 190 mg/mL to about 210 mg/mL, about 195 mg/mL to about 210 mg/mL,
about 200 mg/mL to about 210 mg/mL, about 205 mg/mL to about 210 mg/mL, about
50
mg/mL to about 200 mg/mL, about 55 mg/mL to about 200 mg/mL, about 60 mg/mL to
about 200 mg/mL, about 65 mg/mL to about 200 mg/mL, about 70 mg/mL to about
200
mg/mL, about 75 mg/mL to about 200 mg/mL, about 80 mg/mL to about 200 mg/mL,
about
85 mg/mL to about 200 mg/mL, about 90 mg/mL to about 200 mg/mL, about 95 mg/mL
to
about 200 mg/mL, about 100 mg/mL to about 200 mg/mL, about 105 mg/mL to about
200
mg/mL, about 110 mg/mL to about 200 mg/mL, about 115 mg/mL to about 200 mg/mL,
about 120 mg/mL to about 200 mg/mL, about 125 mg/mL to about 200 mg/mL, about
130
mg/mL to about 200 mg/mL, about 135 mg/mL to about 200 mg/mL, about 140 mg/mL
to
about 200 mg/mL, about 145 mg/mL to about 200 mg/mL, about 150 mg/mL to about
200
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mg/mL, about 155 mg/mL to about 200 mg/mL, about 160 mg/mL to about 200 mg/mL,
about 165 mg/mL to about 200 mg/mL, about 170 mg/mL to about 200 mg/mL, about
175
mg/mL to about 200 mg/mL, about 180 mg/mL to about 200 mg/mL, about 185 mg/mL
to
about 200 mg/mL, about 190 mg/mL to about 200 mg/mL, about 195 mg/mL to about
200
mg/mL, about 50 mg/mL to about 190 mg/mL, about 55 mg/mL to about 190 mg/mL,
about
60 mg/mL to about 190 mg/mL, about 65 mg/mL to about 190 mg/mL, about 70 mg/mL
to
about 190 mg/mL, about 75 mg/mL to about 190 mg/mL, about 80 mg/mL to about
190
mg/mL, about 85 mg/mL to about 190 mg/mL, about 90 mg/mL to about 190 mg/mL,
about
95 mg/mL to about 190 mg/mL, about 100 mg/mL to about 190 mg/mL, about 105
mg/mL to
about 190 mg/mL, about 110 mg/mL to about 190 mg/mL, about 115 mg/mL to about
190
mg/mL, about 120 mg/mL to about 190 mg/mL, about 125 mg/mL to about 190 mg/mL,
about 130 mg/mL to about 190 mg/mL, about 135 mg/mL to about 190 mg/mL, about
140
mg/mL to about 190 mg/mL, about 145 mg/mL to about 190 mg/mL, about 150 mg/mL
to
about 190 mg/mL, about 155 mg/mL to about 190 mg/mL, about 160 mg/mL to about
190
mg/mL, about 165 mg/mL to about 190 mg/mL, about 170 mg/mL to about 190 mg/mL,
about 175 mg/mL to about 190 mg/mL, about 180 mg/mL to about 190 mg/mL, about
185
mg/mL to about 190 mg/mL, about 50 mg/mL to about 180 mg/mL, about 55 mg/mL to
about 180 mg/mL, about 60 mg/mL to about 180 mg/mL, about 65 mg/mL to about
180
mg/mL, about 70 mg/mL to about 180 mg/mL, about 75 mg/mL to about 180 mg/mL,
about
80 mg/mL to about 180 mg/mL, about 85 mg/mL to about 180 mg/mL, about 90 mg/mL
to
about 180 mg/mL, about 95 mg/mL to about 180 mg/mL, about 100 mg/mL to about
180
mg/mL, about 105 mg/mL to about 180 mg/mL, about 110 mg/mL to about 180 mg/mL,
about 115 mg/mL to about 180 mg/mL, about 120 mg/mL to about 180 mg/mL, about
125
mg/mL to about 180 mg/mL, about 130 mg/mL to about 180 mg/mL, about 135 mg/mL
to
about 180 mg/mL, about 140 mg/mL to about 180 mg/mL, about 145 mg/mL to about
180
mg/mL, about 150 mg/mL to about 180 mg/mL, about 155 mg/mL to about 180 mg/mL,
about 160 mg/mL to about 180 mg/mL, about 165 mg/mL to about 180 mg/mL, about
170
mg/mL to about 180 mg/mL, about 175 mg/mL to about 180 mg/mL, about 50 mg/mL
to
about 170 mg/mL, about 55 mg/mL to about 170 mg/mL, about 60 mg/mL to about
170
mg/mL, about 65 mg/mL to about 170 mg/mL, about 70 mg/mL to about 170 mg/mL,
about
75 mg/mL to about 170 mg/mL, about 80 mg/mL to about 170 mg/mL, about 85 mg/mL
to
about 170 mg/mL, about 90 mg/mL to about 170 mg/mL, about 95 mg/mL to about
170
mg/mL, about 100 mg/mL to about 170 mg/mL, about 105 mg/mL to about 170 mg/mL,
about 110 mg/mL to about 170 mg/mL, about 115 mg/mL to about 170 mg/mL, about
120
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mg/mL to about 170 mg/mL, about 125 mg/mL to about 170 mg/mL, about 130 mg/mL
to
about 170 mg/mL, about 135 mg/mL to about 170 mg/mL, about 140 mg/mL to about
170
mg/mL, about 145 mg/mL to about 170 mg/mL, about 150 mg/mL to about 170 mg/mL,
about 155 mg/mL to about 170 mg/mL, about 160 mg/mL to about 170 mg/mL, about
165
mg/mL to about 170 mg/mL, about 50 mg/mL to about 160 mg/mL, about 55 mg/mL to
about 160 mg/mL, about 60 mg/mL to about 160 mg/mL, about 65 mg/mL to about
160
mg/mL, about 70 mg/mL to about 160 mg/mL, about 75 mg/mL to about 160 mg/mL,
about
80 mg/mL to about 160 mg/mL, about 85 mg/mL to about 160 mg/mL, about 90 mg/mL
to
about 160 mg/mL, about 95 mg/mL to about 160 mg/mL, about 100 mg/mL to about
160
mg/mL, about 105 mg/mL to about 160 mg/mL, about 110 mg/mL to about 160 mg/mL,
about 115 mg/mL to about 160 mg/mL, about 120 mg/mL to about 160 mg/mL, about
125
mg/mL to about 160 mg/mL, about 130 mg/mL to about 160 mg/mL, about 135 mg/mL
to
about 160 mg/mL, about 140 mg/mL to about 160 mg/mL, about 145 mg/mL to about
160
mg/mL, about 150 mg/mL to about 160 mg/mL, about 155 mg/mL to about 160 mg/mL,
about 50 mg/mL to about 150 mg/mL, about 55 mg/mL to about 150 mg/mL, about 60
mg/mL to about 150 mg/mL, about 65 mg/mL to about 150 mg/mL, about 70 mg/mL to
about 150 mg/mL, about 75 mg/mL to about 150 mg/mL, about 80 mg/mL to about
150
mg/mL, about 85 mg/mL to about 150 mg/mL, about 90 mg/mL to about 150 mg/mL,
about
95 mg/mL to about 150 mg/mL, about 100 mg/mL to about 150 mg/mL, about 105
mg/mL to
about 150 mg/mL, about 110 mg/mL to about 150 mg/mL, about 115 mg/mL to about
150
mg/mL, about 120 mg/mL to about 150 mg/mL, about 125 mg/mL to about 150 mg/mL,
about 130 mg/mL to about 150 mg/mL, about 135 mg/mL to about 150 mg/mL, about
140
mg/mL to about 150 mg/mL, or about 145 mg/mL to about 150 mg/mL. In some
embodiments, the composition comprising an anti-TL1A antibody at a
concentration of about
50 mg/mL to about 140 mg/mL, about 55 mg/mL to about 140 mg/mL, about 60 mg/mL
to
about 140 mg/mL, about 65 mg/mL to about 140 mg/mL, about 70 mg/mL to about
140
mg/mL, about 75 mg/mL to about 140 mg/mL, about 80 mg/mL to about 140 mg/mL,
about
85 mg/mL to about 140 mg/mL, about 90 mg/mL to about 140 mg/mL, about 95 mg/mL
to
about 140 mg/mL, about 100 mg/mL to about 140 mg/mL, about 105 mg/mL to about
140
mg/mL, about 110 mg/mL to about 140 mg/mL, about 115 mg/mL to about 140 mg/mL,
about 120 mg/mL to about 140 mg/mL, about 125 mg/mL to about 140 mg/mL, about
130
mg/mL to about 140 mg/mL, or about 135 mg/mL to about 140 mg/mL In some
embodiments, the composition comprising an anti-TL1A antibody at a
concentration of about
50 mg/mL to about 130 mg/mL, about 55 mg/mL to about 130 mg/mL, about 60 mg/mL
to
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about 130 mg/mL, about 65 mg/mL to about 130 mg/mL, about 70 mg/mL to about
130
mg/mL, about 75 mg/mL to about 130 mg/mL, about 80 mg/mL to about 130 mg/mL,
about
85 mg/mL to about 130 mg/mL, about 90 mg/mL to about 130 mg/mL, about 95 mg/mL
to
about 130 mg/mL, about 100 mg/mL to about 130 mg/mL, about 105 mg/mL to about
130
mg/mL, about 110 mg/mL to about 130 mg/mL, about 115 mg/mL to about 130 mg/mL,
about 120 mg/mL to about 130 mg/mL, or about 125 mg/mL to about 130 mg/mL. In
some
embodiments, the composition comprising an anti-TLIA antibody at a
concentration of about
50 mg/mL to about 120 mg/mL, about 55 mg/mL to about 120 mg/mL, about 60 mg/mL
to
about 120 mg/mL, about 65 mg/mL to about 120 mg/mL, about 70 mg/mL to about
120
mg/mL, about 75 mg/mL to about 120 mg/mL, about 80 mg/mL to about 120 mg/mL,
about
85 mg/mL to about 120 mg/mL, about 90 mg/mL to about 120 mg/mL, about 95 mg/mL
to
about 120 mg/mL, about 100 mg/mL to about 120 mg/mL, about 105 mg/mL to about
120
mg/mL, about 110 mg/mL to about 120 mg/mL, or about 115 mg/mL to about 120
mg/mL.
In some embodiments, the composition comprising an anti-TLIA antibody at a
concentration
of about 50 mg/mL to about 110 mg/mL, about 55 mg/mL to about 110 mg/mL, about
60
mg/mL to about 110 mg/mL, about 65 mg/mL to about 110 mg/mL, about 70 mg/mL to
about 110 mg/mL, about 75 mg/mL to about 110 mg/mL, about 80 mg/mL to about
110
mg/mL, about 85 mg/mL to about 110 mg/mL, about 90 mg/mL to about 110 mg/mL,
about
95 mg/mL to about 110 mg/mL, about 100 mg/mL to about 110 mg/mL, or about 105
mg/mL
to about 110 mg/mL. In some embodiments, the composition comprising an anti-
TLI A
antibody at a concentration of about 50 mg/mL to about 100 mg/mL, about 55
mg/mL to
about 100 mg/mL, about 60 mg/mL to about 100 mg/mL, about 65 mg/mL to about
100
mg/mL, about 70 mg/mL to about 100 mg/mL, about 75 mg/mL to about 100 mg/mL,
about
80 mg/mL to about 100 mg/mL, about 85 mg/mL to about 100 mg/mL, about 90 mg/mL
to
about 100 mg/mL, about 95 mg/mL to about 100 mg/mL, about 100 mg/mL to about
100
mg/mL, or about 105 mg/mL to about 100 mg/mL. In some embodiments, the
composition
comprising an anti-TLIA antibody at a concentration of about 50 mg/mL to about
90 mg/mL,
about 55 mg/mL to about 90 mg/mL, about 60 mg/mL to about 90 mg/mL, about 65
mg/mL
to about 90 mg/mL, about 70 mg/mL to about 90 mg/mL, about 75 mg/mL to about
90
mg/mL, about 80 mg/mL to about 90 mg/mL, or about 85 mg/mL to about 90 mg/mL.
In
some embodiments, the composition comprising an anti-TL1A antibody at a
concentration of
about 50 mg/mL to about 80 mg/mL, about 55 mg/mL to about 80 mg/mL, about 60
mg/mL
to about 80 mg/mL, about 65 mg/mL to about 80 mg/mL, about 70 mg/mL to about
80
mg/mL, or about 75 mg/mL to about 80 mg/mL. In some embodiments, the
composition
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comprising an anti-TL1A antibody at a concentration of about 50 mg/mL to about
70 mg/mL,
about 55 mg/mL to about 70 mg/mL, about 60 mg/mL to about 70 mg/mL, or about
65
mg/mL to about 70 mg/mL. In some embodiments, the composition comprising an
anti-
TL1A antibody at a concentration of about 50 mg/mL to about 55 mg/mL, about 50
mg/mL
to about 60 mg/mL, or about 55 mg/mL to about 60 mg/mL.
1002731 The composition provided herein may have a viscosity of less than or
about 20
centipoise (cP). The composition may have a viscosity of less than or about 15
centipoise
(cP). The composition may have a viscosity of less than or about 10 centipoise
(cP). For
instance, the composition has a viscosity of less than or about 20, 19, 18,
17, 16, 15, 14, 13,
12, 11, 10, 9, 8, 7,6, 5, 4, 3, or 2 cP. The composition may have a viscosity
of at least about
1, 2 or 3 cP. Further example viscosities include about 1 cP to about 2 cP,
about 1 cP to about
3 cP, about 1 cP to about 4 cP, about 1 cP to about 5 cP, about 1 cP to about
6 cP, about 1 cP
to about 7 cP, about 1 cP to about 8 cP, about 1 cP to about 9 cP, about 1 cP
to about 10 cP,
about 1 cP to about 11 cP, about 1 cP to about 12 cP, about 1 cP to about 13
cP, about 1 cP to
about 14 cP, about 1 cP to about 15 cP, about 1 cP to about 16 cP, about 1 cP
to about 17 cP,
about 1 cP to about 18 cP, about 1 cP to about 19 cP, about 1 cP to about 20
cP, about 2 cP to
about 5 cP, about 2 cP to about 6 cP, about 2 cP to about 7 cP, about 2 cP to
about 8 cP, about
2 cP to about 9 cP, about 2 cP to about 10 cP, about 2 cP to about 11 cP,
about 2 cP to about
12 cP, about 2 cP to about 13 cP, about 2 cP to about 14 cP, about 2 cP to
about 15 cP, about
2 cP to about 16 cP, about 2 cP to about 17 cP, about 2 cP to about 18 cP,
about 2 cP to about
19 cP, about 2 cP to about 20 cP, about 3 cP to about 5 cP, about 3 cP to
about 6 cP, about 3
cP to about 7 cP, about 3 cP to about 8 cP, about 3 cP to about 9 cP, about 3
cP to about 10
cP, about 3 cP to about 11 cP, about 3 cP to about 12 cP, about 3 cP to about
13 cP, about 3
cP to about 14 cP, about 3 cP to about 15 cP, about 3 cP to about 16 cP, about
3 cP to about
17 cP, about 3 cP to about 18 cP, about 3 cP to about 19 cP, about cP to about
20 cP, about 4
cP to about 5 cP, about 4 cP to about 6 cP, about 4 cP to about 7 cP, about 4
cP to about 8 cP,
about 4 cP to about 9 cP, or about 4 cP to about 10 cP. about 4 cP to about 11
cP, about 4 cP
to about 12 cP, about 4 cP to about 13 cP, about 4 cP to about 14 cP, about 4
cP to about 15
cP, about 4 cP to about 16 cP, about 4 cP to about 17 cP, about 4 cP to about
18 cP, about 4
cP to about 19 cP, about 4 cP to about 20 cP, about 5 cP to about 10 cP, about
5 cP to about
11 cP, about 5 cP to about 12 cP, about 5 cP to about 13 cP, about 5 cP to
about 14 cP, about
cP to about 15 cP, about 5 cP to about 16 cP, about 5 cP to about 17 cP, about
5 cP to about
18 cP, about 5 cP to about 19 cP, about 5 cP to about 20 cP, about 6 cP to
about 10 cP, about
6 cP to about 11 cP, about 6 cP to about 12 cP, about 6 cP to about 13 cP,
about 6 cP to about
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14 cP, about 6 cP to about 15 cP, about 6 cP to about 16 cP, about 6 cP to
about 17 cP, about
6 cP to about 18 cP, about 6 cP to about 19 cP, about 6 cP to about 20 cP,
about 7 cP to about
cP, about 7 cP to about 11 cP, about 7 cP to about 12 cP, about 7 cP to about
13 cP, about
7 cP to about 14 cP, about 7 cP to about 15 cP, about 7 cP to about 16 cP,
about 7 cP to about
17 cP, about 7 cP to about 18 cP, about 7 cP to about 19 cP, about 7 cP to
about 20 cP, about
8 cP to about 10 cP, about 8 cP to about 11 cP, about 8 cP to about 12 cP,
about 8 cP to about
13 cP, about 8 cP to about 14 cP, about 8 cP to about 15 cP, about 8 cP to
about 16 cP, about
8 cP to about 17 cP, about 8 cP to about 18 cP, about 8 cP to about 19 cP, or
about 8 cP to
about 20 cP. In some embodiments, a centipoise as used herein is a millipascal-
second
(mPa.$).
1002741 In certain embodiments, provided herein is a pharmaceutical
composition
comprising a therapeutically effective dose of an anti-TL1A antibody having a
total volume
of less than or equal to about 2.5 mL. In some embodiments, the pharmaceutical
composition
comprises a therapeutically effective dose of an anti-TL1A antibody having a
total volume of
less than or equal to about 2 mL. The total volume may be less than or equal
to about 9.0,8.9,
8.8, 8.7, 8.6, 8.5,8.4, 8.3, 8.2, 8.1,8.0, 7.9, 7.8, 7.7,7.6, 7.5, 7.4,
7.3,7.2, 7.1, 7.0, 6.9,6.8,
6.7, 6.6, 6.5, 6.4,6.3, 6.2, 6.1, 6.0,5.9, 5.8, 5.7, 5.6,5.5, 5.4, 5.3, 5.2,
5.1, 5.0, 4.9, 4.8,4.7,
4.6, 4.5, 4.4, 4.3,4.2, 4.1, 4, 3.9, 3.8,3.7, 3.6, 3.5, 3.4,3.3, 3.2, 3.1,
3.0,2.9, 2.8, 2.7, 2.6,2.5,
2.4, 2.3, 2.2, 2.1, 2.0, 1.9, 1.8, 1.7,1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.9,
or 0.8 mL. The total
volume may be at least about 0.5 mL. The total volume may be about 0.5 mL to
about 3 mL,
about 0.5 mL to about 2.9 mL, about 0.5 mL to about 2.8 mL, about 0.5 mL to
about 2.7 mL,
about 0.5 mL to about 2.6 mL, about 0.5 mL to about 2.5 mL, about 0.5 mL to
about 2.4 mL,
about 0.5 mL to about 2.3 mL, about 0.5 mL to about 2.2 mL, about 0.5 mL to
about 2.1 mL,
about 0.5 mL to about 2.0 mL, about 0.5 mL to about 1.9 mL, about 0.5 mL to
about 1.8 mL,
about 0.5 mL to about 1.7 mL, about 0.5 mL to about 1.6 mL, about 0.5 mL to
about 1.5 mL,
about 0.5 mL to about 1.4 mL, about 0.5 mL to about 1.3 mL, about 0.5 mL to
about 1.2 mL,
about 0.5 mL to about 1.1 mL, about 0.5 mL to about 1.0 mL, about 0.5 mL to
about 0.9 mL,
about 0.5 mL to about 0.8 mL, about 0.6 mL to about 3 mL, about 0.6 mL to
about 2.9 mL,
about 0.6 mL to about 2.8 mL, about 0.6 mL to about 2.7 mL, about 0.6 mL to
about 2.6 mL,
about 0.6 mL to about 2.5 mL, about 0.6 mL to about 2.4 mL, about 0.6 mL to
about 2.3 mL,
about 0.6 mL to about 2.2 mL, about 0.6 mL to about 2.1 mL, about 0.6 mL to
about 2.0 mL,
about 0.6 mL to about 1.9 mL, about 0.6 mL to about 1.8 mL, about 0.6 mL to
about 1.7 mL,
about 0.6 mL to about 1.6 mL, 0.6 mL to about 1.5 mL, about 0.6 mL to about
1.4 mL, about
0.6 mL to about 1.3 mL, about 0.6 mL to about 1.2 mL, about 0.6 mL to about
1.1 mL, about
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0.6 mL to about 1.0 mL, about 0.6 mL to about 0.9 mL, about 0.6 mL to about
0.8 mL, about
0.7 mL to about 3 mL, about 0.7 mL to about 2.9 mL, about 0.7 mL to about 2.8
mL, about
0.7 mL to about 2.7 mL, about 0.7 mL to about 2.6 mL, about 0.7 mL to about
2.5 mL, about
0.7 mL to about 2.4 mL, about 0.7 mL to about 2.3 mL, about 0.7 mL to about
2.2 mL, about
0.7 mL to about 2.1 mL, about 0.7 mL to about 2.0 mL, about 0.7 mL to about
1.9 mL, about
0.7 mL to about 1.8 mL, about 0.7 mL to about 1.7 mL, about 0.7 mL to about
1.6 mL, about
0.7 mL to about 1.5 mL, about 0.7 mL to about 1.4 mL, about 0.7 mL to about
1.3 mL, about
0.7 mL to about 1.2 mL, about 0.7 mL to about 1.1 mL, about 0.7 mL to about
1.0 mL, about
0.7 mL to about 0.9 mL, about 0.7 mL to about 0.8 mL, about 3 mL to about 10
mL, about 3
mL to about 9.5 mL, about 3 mL to about 9.0 mL, about 3 mL to about 8.5 mL,
about 3 mL
to about 8.0 mL, about 3 mL to about 7.5 mL, about 3 mL to about 7.0 mL, about
3 mL to
about 6.5 mL, about 3 mL to about 6 mL, about 3 mL to about 5.5 mL, about 3 mL
to about
5.0 mL, about 3 mL to about 4.5 mL, about 3 mL to about 4 mL, about 3 mL to
about 3.5
mL, about 3 .5 mL to about 10 mL, about 3.5 mL to about 9.5 mL, about 3.5 mL
to about 9.0
mL, about 3 .5 mL to about 8.5 mL, about 3.5 mL to about 8.0 mL, about 3.5 mL
to about 7.5
mL, about 3 .5 mL to about 7.0 mL, about 3.5 mL to about 6.5 mL, about 3.5 mL
to about 6
mL, about 3 .5 mL to about 5.5 mL, about 3.5 mL to about 5.0 mL, about 3.5 mL
to about 4.5
mL, about 3.5 mL to about 4 mL, about 4.0 mL to about 10 mL, about 4.0 mL to
about 9.5
mL, about 4.0 mL to about 9.0 mL, about 4.0 mL to about 8.5 mL, about 4.0 mL
to about 8.0
mL, about 4.0 mL to about 7.5 mL, about 4.0 mL to about 7.0 mL, about 4.0 mL
to about 6.5
mL, about 4.0 mL to about 6 mL, about 4.0 mL to about 5.5 mL, about 4.0 mL to
about 5.0
mL, about 4.0 mL to about 4.5 mL, about 4.5 mL to about 1 0 mL, about 4.5 mL
to about 9.5
mL, about 4.5 mL to about 9.0 mL, about 4.5 mL to about 8.5 mL, about 4.5 mL
to about 8.0
mL, about 4.5 mL to about 7.5 mL, about 4.5 mL to about 7.0 mL, about 4.5 mL
to about 6.5
mL, about 4.5 mL to about 6 mL, about 4.5 mL to about 5.5 mL, about 4.5 mL to
about 5.0
mL, about 5 mL to about 10 mL, about 5 mL to about 9.5 mL, about 5 mL to about
9.0 mL,
about 5 mL to about 8.5 mL, about 5 mL to about 8.0 mL, about 5 mL to about
7.5 mL, about
mL to about 7.0 mL, about 5 mL to about 6.5 mL, about 5 mL to about 6 mL,
about 5 mL
to about 5.5 mL, about 5.5 mL to about 10 mL, about 5.5 mL to about 9.5 mL,
about 5.5 mL
to about 9.0 mL, about 5.5 mL to about 8.5 mL, about 5.5 mL to about 8.0 mL,
about 5.5 mL
to about 7.5 mL, about 5.5 mL to about 7.0 mL, about 5.5 mL to about 6.5 mL,
about 5.5 mL
to about 6 mL, about 6.0 mL to about 10 mL, about 6.0 mL to about 9.5 mL,
about 6.0 mL to
about 9.0 mL, about 6.0 mL to about 8.5 mL, about 6.0 mL to about 8.0 mL,
about 6.0 mL to
about 7.5 mL, about 6.0 mL to about 7.0 mL, about 6.0 mL to about 6.5 mL,
about 6.5 mL to
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about 10 mL, about 6.5 mL to about 9.5 mL, about 6.5 mL to about 9.0 mL, about
6.5 mL to
about 8.5 mL, about 6.5 mL to about 8.0 mL, about 6.5 mL to about 7.5 mL,
about 6.5 mL to
about 7.0 mL, about 7.0 mL to about 10 mL, about 7.0 mL to about 9.5 mL, about
7.0 mL to
about 9.0 mL, about 7.0 mL to about 8.5 mL, about 7.0 mL to about 8.0 mL,
about 7.0 mL to
about 7.5 mL, about 7.5 mL to about 10 mL, about 7.5 mL to about 9.5 mL, about
7.5 mL to
about 9.0 mL, about 7.5 mL to about 8.5 mL, about 7.5 mL to about 8.0 mL,
about 8.0 mL to
about 10 mL, about 8.0 mL to about 9.5 mL, about 8.0 mL to about 9.0 mL, about
8.0 mL to
about 8.5 mL, about 8.5 mL to about 10 mL, about 8.5 mL to about 9.5 mL, about
8.5 mL to
about 9.0 mL, about 9 mL to about 10 mL, about 9 mL to about 9.5 mL, or about
9.5 mL to
about 10 mL. The composition may have a viscosity of less than or about 10
centipoise (cP).
For instance, the composition has a viscosity of less than or about 20, 19,
18, 17, 16, 15, 14,
13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2 cP. The composition may have a
viscosity of at least
about 1, 2 or 3 cP. Further example viscosities include about 1 cP to about 2
cP, about 1 cP to
about 3 cP, about 1 cP to about 4 cP, about 1 cP to about 5 cP, about 1 cP to
about 6 cP, about
1 cP to about 7 cP, about 1 cP to about 8 cP, about 1 cP to about 9 cP, about
1 cP to about 10
cP, about 2 cP to about 5 cP, about 2 cP to about 6 cP, about 2 cP to about 7
cP, about 2 cP to
about 8 cP, about 2 cP to about 9 cP, about 2 cP to about 10 cP, about 3 cP to
about 5 cP,
about 3 cP to about 6 cP, about 3 cP to about 7 cP, about 3 cP to about 8 cP,
about 3 cP to
about 9 cP, about 3 cP to about 10 cP, about 4 cP to about 5 cP, about 4 cP to
about 6 cP,
about 4 cP to about 7 cP, about 4 cP to about 8 cP, about 4 cP to about 9 cP,
or about 4 cP to
about 10 cP, In some embodiments, the therapeutically effective dose is at
least about 150 mg
anti-TL1A antibody. In some cases, the therapeutically effective dose is about
or at least
about 150, 155, 160, 165, 170, 175, 180, 185, 190, 195,200,205,210, 215, 220,
225, 230,
235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285,290,
295,300,300,350,400,450,
500, 550, 600, 650, 700, 750,800, 850, 900, 950, 1000, 1100, 1200, 1300, 1400,
1500,1600,
1700, 1800, 1900, or 2000 mg of anti-TL1A. In some cases, the therapeutically
effective dose
is about 150 mg to about 2000 mg, about 150 mg to about 1750 mg, about 150 mg
to about
1500 mg, about 150 mg to about 1250 mg, about 150 mg to about 1000 mg, about
150 mg to
about 750 mg, about 150 mg to about 500 mg, about 150 mg to about 450 mgõ
about 150 mg
to about 400 mg, about 150 mg to about 350 mg, about 150 mg to about 300 mg,
about 150
mg to about 250 mg, or about 150 mg to about 200 mg anti-TL1A. In some
embodiments, the
pharmaceutical composition comprises about 50 mg/mL to about 250 mg/mL, about
55
mg/mL to about 250 mg/mL, about 60 mg/mL to about 250 mg/mL, about 65 mg/mL to
about 250 mg/mL, about 70 mg/mL to about 250 mg/mL, about 75 mg/mL to about
250
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mg/mL, about 80 mg/mL to about 250 mg/mL, about 85 mg/mL to about 250 mg/mL,
about
90 mg/mL to about 250 mg/mL, about 95 mg/mL to about 250 mg/mL, about 100
mg/mL to
about 250 mg/mL, about 105 mg/mL to about 250 mg/mL, about 110 m g/mL to about
250
mg/mL, about 115 mg/mL to about 250 mg/mL, about 120 mg/mL to about 250 mg/mL,
about 125 mg/mL to about 250 mg/mL, about 130 mg/mL to about 250 mg/mL, about
135
mg/mL to about 250 mg/mL, about 140 mg/mL to about 250 mg/mL, about 145 mg/mL
to
about 250 mg/mL, about 150 mg/mL to about 250 mg/mL, about 155 mg/mL to about
250
mg/mL, about 160 mg/mL to about 250 mg/mL, about 165 mg/mL to about 250 mg/mL,
about 170 mg/mL to about 250 mg/mL, about 175 mg/mL to about 250 mg/mL, about
180
mg/mL to about 250 mg/mL, about 185 mg/mL to about 250 mg/mL, about 190 mg/mL
to
about 250 mg/mL, about 195 mg/mL to about 250 mg/mL, about 200 mg/mL to about
250
mg/mL, about 205 mg/mL to about 250 mg/mL, about 210 mg/mL to about 250 mg/mL,
about 215 mg/mL to about 250 mg/mL, about 220 mg/mL to about 250 mg/mL, about
225
mg/mL to about 250 mg/mL, about 230 mg/mL to about 250 mg/mL, about 235 mg/mL
to
about 250 mg/mL, about 240 mg/mL to about 250 mg/mL, about 245 mg/mL to about
250
mg/mL, about 50 mg/mL to about 240 mg/mL, about 55 mg/mL to about 240 mg/mL,
about
60 mg/mL to about 240 mg/mL, about 65 mg/mL to about 240 mg/mL, about 70 mg/mL
to
about 240 mg/mL, about 75 mg/mL to about 240 mg/mL, about 80 mg/mL to about
240
mg/mL, about 85 mg/mL to about 240 mg/mL, about 90 mg/mL to about 240 mg/mL,
about
95 mg/mL to about 240 mg/mL, about 100 mg/mL to about 240 mg/mL, about 105
mg/mL to
about 240 mg/mL, about 110 mg/mL to about 240 mg/mL, about 115 mg/mL to about
240
mg/mL, about 120 mg/mL to about 240 mg/mL, about 125 mg/mL to about 240 mg/mL,
about 130 mg/mL to about 240 mg/mL, about 135 mg/mL to about 240 mg/mL, about
140
mg/mL to about 240 mg/mL, about 145 mg/mL to about 240 mg/mL, about 150 mg/mL
to
about 240 mg/mL, about 155 mg/mL to about 240 mg/mL, about 160 mg/mL to about
240
mg/mL, about 165 mg/mL to about 240 mg/mL, about 170 mg/mL to about 240 mg/mL,
about 175 mg/mL to about 240 mg/mL, about 180 mg/mL to about 240 mg/mL, about
185
mg/mL to about 240 mg/mL, about 190 mg/mL to about 240 mg/mL, about 195 mg/mL
to
about 240 mg/mL, about 200 mg/mL to about 240 mg/mL, about 205 mg/mL to about
240
mg/mL, about 210 mg/mL to about 240 mg/mL, about 215 mg/mL to ab out 240
mg/mL,
about 220 mg/mL to about 240 mg/mL, about 225 mg/mL to about 240 mg/mL, about
230
mg/mL to about 240 mg/mL, about 235 mg/mL to about 240 mg/mL, about 50 mg/mL
to
about 230 mg/mL, about 55 mg/mL to about 230 mg/mL, about 60 mg/mL to about
230
mg/mL, about 65 mg/mL to about 230 mg/mL, about 70 mg/mL to about 230 mg/mL,
about
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75 mg/mL to about 230 mg/mL, about 80 mg/mL to about 230 mg/mL, about 85 mg/mL
to
about 230 mg/mL, about 90 mg/mL to about 230 mg/mL, about 95 mg/mL to about
230
mg/mL, about 100 mg/mL to about 230 mg/mL, about 105 mg/mL to about 230 mg/mL,
about 110 mg/mL to about 230 mg/mL, about 115 mg/mL to about 230 mg/mL, about
120
mg/mL to about 230 mg/mL, about 125 mg/mL to about 230 mg/mL, about 130 mg/mL
to
about 230 mg/mL, about 135 mg/mL to about 230 mg/mL, about 140 mg/mL to about
230
mg/mL, about 145 mg/mL to about 230 mg/mL, about 150 mg/mL to about 230 mg/mL,
about 155 mg/mL to about 230 mg/mL, about 160 mg/mL to about 230 mg/mL, about
165
mg/mL to about 230 mg/mL, about 170 mg/mL to about 230 mg/mL, about 175 mg/mL
to
about 230 mg/mL, about 180 mg/mL to about 230 mg/mL, about 185 mg/mL to about
230
mg/mL, about 190 mg/mL to about 230 mg/mL, about 195 mg/mL to about 230 mg/mL,
about 200 mg/mL to about 230 mg/mL, about 205 mg/mL to about 230 mg/mL, about
210
mg/mL to about 230 mg/mL, about 215 mg/mL to about 230 mg/mL, about 220 mg/mL
to
about 230 mg/mL, about 225 mg/mL to about 230 mg/mL, about 50 mg/mL to about
220
mg/mL, about 55 mg/mL to about 220 mg/mL, about 60 mg/mL to about 220 mg/mL,
about
65 mg/mL to about 220 mg/mL, about 70 mg/mL to about 220 mg/mL, about 75 mg/mL
to
about 220 mg/mL, about 80 mg/mL to about 220 mg/mL, about 85 mg/mL to about
220
mg/mL, about 90 mg/mL to about 220 mg/mL, about 95 mg/mL to about 220 mg/mL,
about
100 mg/mL to about 220 mg/mL, about 105 mg/mL to about 220 mg/mL, about 110
mg/mL
to about 220 mg/mL, about 115 mg/mL to about 220 mg/mL, about 120 mg/mL to
about 220
mg/mL, about 125 mg/mL to about 220 mg/mL, about 130 mg/mL to about 220 mg/mL,
about 135 mg/mL to about 220 mg/mL, about 140 mg/mL to about 220 mg/mL, about
145
mg/mL to about 220 mg/mL, about 150 mg/mL to about 220 mg/mL, about 155 mg/mL
to
about 220 mg/mL, about 160 mg/mL to about 220 mg/mL, about 165 mg/mL to about
220
mg/mL, about 170 mg/mL to about 220 mg/mL, about 175 mg/mL to about 220 mg/mL,
about 180 mg/mL to about 220 mg/mL, about 185 mg/mL to about 220 mg/mL, about
190
mg/mL to about 220 mg/mL, about 195 mg/mL to about 220 mg/mL, about 200 mg/mL
to
about 220 mg/mL, about 205 mg/mL to about 220 mg/mL, about 210 mg/mL to about
220
mg/mL, about 215 mg/mL to about 220 mg/mL, about 50 mg/mL to about 210 mg/mL,
about
55 mg/mL to about 210 mg/mL, about 60 mg/mL to about 210 mg/mL, about 65 mg/mL
to
about 210 mg/mL, about 70 mg/mL to about 210 mg/mL, about 75 mg/mL to about
210
mg/mL, about 80 mg/mL to about 210 mg/mL, about 85 mg/mL to about 210 mg/mL,
about
90 mg/mL to about 210 mg/mL, about 95 mg/mL to about 210 mg/mL, about 100
mg/mL to
about 210 mg/mL, about 105 mg/mL to about 210 mg/mL, about 110 mg/mL to about
210
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mg/mL, about 115 mg/mL to about 210 mg/mL, about 120 mg/mL to about 210 mg/mL,
about 125 mg/mL to about 210 mg/mL, about 130 mg/mL to about 210 mg/mL, about
135
mg/mL to about 210 mg/mL, about 140 mg/mL to about 210 mg/mL, about 145 mg/mL
to
about 210 mg/mL, about 150 mg/mL to about 210 mg/mL, about 155 mg/mL to about
210
mg/mL, about 160 mg/mL to about 210 mg/mL, about 165 mg/mL to ab out 210
mg/mL,
about 170 mg/mL to about 210 mg/mL, about 175 mg/mL to about 210 mg/mL, about
180
mg/mL to about 210 mg/mL, about 185 mg/mL to about 210 mg/mL, about 190 mg/mL
to
about 210 mg/mL, about 195 mg/mL to about 210 mg/mL, about 200 mg/mL to about
210
mg/mL, about 205 mg/mL to about 210 mg/mL, about 50 mg/mL to about 200 mg/mL,
about
55 mg/mL to about 200 mg/mL, about 60 mg/mL to about 200 mg/mL, about 65 mg/mL
to
about 200 mg/mL, about 70 mg/mL to about 200 mg/mL, about 75 mg/mL to about
200
mg/mL, about 80 mg/mL to about 200 mg/mL, about 85 mg/mL to about 200 mg/mL,
about
90 mg/mL to about 200 mg/mL, about 95 mg/mL to about 200 mg/mL, about 100
mg/mL to
about 200 mg/mL, about 105 mg/mL to about 200 mg/mL, about 110 mg/mL to about
200
mg/mL, about 115 mg/mL to about 200 mg/mL, about 120 mg/mL to about 200 mg/mL,
about 125 mg/mL to about 200 mg/mL, about 130 mg/mL to about 200 mg/mL, about
135
mg/mL to about 200 mg/mL, about 140 mg/mL to about 200 mg/mL, about 145 mg/mL
to
about 200 mg/mL, about 150 mg/mL to about 200 mg/mL, about 155 mg/mL to about
200
mg/mL, about 160 mg/mL to about 200 mg/mL, about 165 mg/mL to about 200 mg/mL,
about 170 mg/mL to about 200 mg/mL, about 175 mg/mL to about 200 mg/mL, about
180
mg/mL to about 200 mg/mL, about 185 mg/mL to about 200 mg/mL, about 190 mg/mL
to
about 200 mg/mL, about 195 mg/mL to about 200 mg/mL, about 50 mg/mL to about
190
mg/mL, about 55 mg/mL to about 190 mg/mL, about 60 mg/mL to about 190 mg/mL,
about
65 mg/mL to about 190 mg/mL, about 70 mg/mL to about 190 mg/mL, about 75 mg/mL
to
about 190 mg/mL, about 80 mg/mL to about 190 mg/mL, about 85 mg/mL to about
190
mg/mL, about 90 mg/mL to about 190 mg/mL, about 95 mg/mL to about 190 mg/mL,
about
100 mg/mL to about 190 mg/mL, about 105 mg/mL to about 190 mg/mL, about 110
mg/mL
to about 190 mg/mL, about 115 mg/mL to about 190 mg/mL, about 120 mg/mL to
about 190
mg/mL, about 125 mg/mL to about 190 mg/mL, about 130 mg/mL to about 190 mg/mL,
about 135 mg/mL to about 190 mg/mL, about 140 mg/mL to about 190 mg/mL, about
145
mg/mL to about 190 mg/mL, about 150 mg/mL to about 190 mg/mL, about 155 mg/mL
to
about 190 mg/mL, about 160 mg/mL to about 190 mg/mL, about 165 mg/mL to about
190
mg/mL, about 170 mg/mL to about 190 mg/mL, about 175 mg/mL to about 190 mg/mL,
about 180 mg/mL to about 190 mg/mL, about 185 mg/mL to about 190 mg/mL, about
50
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mg/mL to about 180 mg/mL, about 55 mg/mL to about 180 mg/mL, about 60 mg/mL to
about 180 mg/mL, about 65 mg/mL to about 180 mg/mL, about 70 mg/mL to about
180
mg/mL, about 75 mg/mL to about 180 mg/mL, about 80 mg/mL to about 180 mg/mL,
about
85 mg/mL to about 180 mg/mL, about 90 mg/mL to about 180 mg/mL, about 95 mg/mL
to
about 180 mg/mL, about 100 mg/mL to about 180 mg/mL, about 105 mg/mL to about
180
mg/mL, about 110 mg/mL to about 180 mg/mL, about 115 mg/mL to about 180 mg/mL,
about 120 mg/mL to about 180 mg/mL, about 125 mg/mL to about 180 mg/mL, about
130
mg/mL to about 180 mg/mL, about 135 mg/mL to about 180 mg/mL, about 140 mg/mL
to
about 180 mg/mL, about 145 mg/mL to about 180 mg/mL, about 150 mg/mL to about
180
mg/mL, about 155 mg/mL to about 180 mg/mL, about 160 mg/mL to about 180 mg/mL,
about 165 mg/mL to about 180 mg/mL, about 170 mg/mL to about 180 mg/mL, about
175
mg/mL to about 180 mg/mL, about 50 mg/mL to about 170 mg/mL, about 55 mg/mL to
about 170 mg/mL, about 60 mg/mL to about 170 mg/mL, about 65 mg/mL to about
170
mg/mL, about 70 mg/mL to about 170 mg/mL, about 75 mg/mL to about 170 mg/mL,
about
80 mg/mL to about 170 mg/mL, about 85 mg/mL to about 170 mg/mL, about 90 mg/mL
to
about 170 mg/mL, about 95 mg/mL to about 170 mg/mL, about 100 mg/mL to about
170
mg/mL, about 105 mg/mL to about 170 mg/mL, about 110 mg/mL to about 170 mg/mL,
about 115 mg/mL to about 170 mg/mL, about 120 mg/mL to about 170 mg/mL, about
125
mg/mL to about 170 mg/mL, about 130 mg/mL to about 170 mg/mL, about 135 mg/mL
to
about 170 mg/mL, about 140 mg/mL to about 170 mg/mL, about 145 mg/mL to about
170
mg/mL, about 150 mg/mL to about 170 mg/mL, about 155 mg/mL to about 170 mg/mL,
about 160 mg/mL to about 170 mg/mL, about 165 mg/mL to about 170 mg/mL, about
50
mg/mL to about 160 mg/mL, about 55 mg/mL to about 160 mg/mL, about 60 mg/mL to
about 160 mg/mL, about 65 mg/mL to about 160 mg/mL, about 70 mg/mL to about
160
mg/mL, about 75 mg/mL to about 160 mg/mL, about 80 mg/mL to about 160 mg/mL,
about
85 mg/mL to about 160 mg/mL, about 90 mg/mL to about 160 mg/mL, about 95 mg/mL
to
about 160 mg/mL, about 100 mg/mL to about 160 mg/mL, about 105 mg/mL to about
160
mg/mL, about 110 mg/mL to about 160 mg/mL, about 115 mg/mL to about 160 mg/mL,
about 120 mg/mL to about 160 mg/mL, about 125 mg/mL to about 160 mg/mL, about
130
mg/mL to about 160 mg/mL, about 135 mg/mL to about 160 mg/mL, about 140 mg/mL
to
about 160 mg/mL, about 145 mg/mL to about 160 mg/mL, about 150 mg/mL to about
160
mg/mL, about 155 mg/mL to about 160 mg/mL, about 50 mg/mL to about 150 mg/mL,
about
55 mg/mL to about 150 mg/mL, about 60 mg/mL to about 150 mg/mL, about 65 mg/mL
to
about 150 mg/mL, about 70 mg/mL to about 150 mg/mL, about 75 mg/mL to about
150
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mg/mL, about 80 mg/mL to about 150 mg/mL, about 85 mg/mL to about 150 mg/mL,
about
90 mg/mL to about 150 mg/mL, about 95 mg/mL to about 150 mg/mL, about 100
mg/mL to
about 150 mg/mL, about 105 mg/mL to about 150 mg/mL, about 110 mg/mL to about
150
mg/mL, about 115 mg/mL to about 150 mg/mL, about 120 mg/mL to about 150 mg/mL,
about 125 mg/mL to about 150 mg/mL, about 130 mg/mL to about 150 mg/mL, about
135
mg/mL to about 150 mg/mL, about 140 mg/mL to about 150 mg/mL, about 145 mg/mL
to
about 150 mg/mL, about 50 mg/mL to about 140 mg/mL, about 55 mg/mL to about
140
mg/mL, about 60 mg/mL to about 140 mg/mL, about 65 mg/mL to about 140 mg/mL,
about
70 mg/mL to about 140 mg/mL, about 75 mg/mL to about 140 mg/mL, about 80 mg/mL
to
about 140 mg/mL, about 85 mg/mL to about 140 mg/mL, about 90 mg/mL to about
140
mg/mL, about 95 mg/mL to about 140 mg/mL, about 100 mg/mL to about 140 mg/mL,
about
105 mg/mL to about 140 mg/mL, about 110 mg/mL to about 140 mg/mL, about 115
mg/mL
to about 140 mg/mL, about 120 mg/mL to about 140 mg/mL, about 125 mg/mL to
about 140
mg/mL, about 130 mg/mL to about 140 mg/mL, about 135 mg/mL to about 140 mg/mL,
about 50 mg/mL to about 130 mg/mL, about 55 mg/mL to about 130 mg/mL, about 60
mg/mL to about 130 mg/mL, about 65 mg/mL to about 130 mg/mL, about 70 mg/mL to
about 130 mg/mL, about 75 mg/mL to about 130 mg/mL, about 80 mg/mL to about
130
mg/mL, about 85 mg/mL to about 130 mg/mL, about 90 mg/mL to about 130 mg/mL,
about
95 mg/mL to about 130 mg/mL, about 100 mg/mL to about 130 mg/mL, about 105
mg/mL to
about 130 mg/mL, about 110 mg/mL to about 130 mg/mL, about 115 mg/mL to about
130
mg/mL, about 120 mg/mL to about 130 mg/mL, or about 125 mg/mL to about 130
mg/mL,
about 50 mg/mL to about 120 mg/mL, about 55 mg/mL to about 120 mg/mL, about 60
mg/mL to about 120 mg/mL, about 65 mg/mL to about 120 mg/mL, about 70 mg/mL to
about 120 mg/mL, about 75 mg/mL to about 120 mg/mL, about 80 mg/mL to about
120
mg/mL, about 85 mg/mL to about 120 mg/mL, about 90 mg/mL to about 120 mg/mL,
about
95 mg/mL to about 120 mg/mL, about 100 mg/mL to about 120 mg/mL, about 105
mg/mL to
about 120 mg/mL, about 110 mg/mL to about 120 mg/mL, about 115 mg/mL to about
120
mg/mL, about 50 mg/mL to about 110 mg/mL, about 55 mg/mL to about 110 mg/mL,
about
60 mg/mL to about 110 mg/mL, about 65 mg/mL to about 110 mg/mL, about 70 mg/mL
to
about 110 mg/mL, about 75 mg/mL to about 110 mg/mL, about 80 mg/mL to about
110
mg/mL, about 85 mg/mL to about 110 mg/mL, about 90 mg/mL to about 110 mg/mL,
about
95 mg/mL to about 110 mg/mL, about 100 mg/mL to about 110 mg/mL, about 105
mg/mL to
about 110 mg/mL, about 50 mg/mL to about 100 mg/mL, about 55 mg/mL to about
100
mg/mL, about 60 mg/mL to about 100 mg/mL, about 65 mg/mL to about 100 mg/mL,
about
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70 mg/mL to about 100 mg/mL, about 75 mg/mL to about 100 mg/mL, about 80 mg/mL
to
about 100 mg/mL, about 85 mg/mL to about 100 mg/mL, about 90 mg/mL to about
100
mg/mL, about 95 mg/mL to about 100 mg/mL, about 100 mg/mL to about 100 mg/mL,
about
105 mg/mL to about 100 mg/mL, about 50 mg/mL to about 90 mg/mL, about 55 mg/mL
to
about 90 mg/mL, about 60 mg/mL to about 90 mg/mL, about 65 mg/mL to about 90
mg/mL,
about 70 mg/mL to about 90 mg/mL, about 75 mg/mL to about 90 mg/mL, about 80
mg/mL
to about 90 mg/mL, about 85 mg/mL to about 90 mg/mL, about 50 mg/mL to about
80
mg/mL, about 55 mg/mL to about 80 mg/mL, about 60 mg/mL to about 80 mg/mL,
about 65
mg/mL to about 80 mg/mL, about 70 mg/mL to about 80 mg/mL, about 75 mg/mL to
about
80 mg/mL, about 50 mg/mL to about 70 mg/mL, about 55 mg/ mL to about 70 mg/mL,
about
60 mg/mL to about 70 mg/mL, about 65 mg/mL to about 70 mg/mL, about 50 mg/mL
to
about 60 mg/mL, about 55 mg/mL to about 60 mg/mL, or about 50 mg/mL to about
55
mg/mL anti-TL1A. In some embodiments, the concentration of anti-TL1A is about
or greater
than about 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125,
130, 135, 140,
145, 155, 160,165,170,175,180,185,190, 195, 200,205,210,215,220, 225,230, 235,
240, 245, 250, 255, 260, 265,270, 275, 280, 285, 290, 295, or 300 mg/mL.
1002751 In certain embodiments, provided herein is a pharmaceutical
composition for
subcutaneous administration comprising an anti-TL1A antibody, wherein at least
about 150
mg of the anti-TL1A antibody is present in the composition. For instance,
about 150 mg to
about 2000 mg, about 150 mg to about 1750 mg, about 150 mg to about 1500 mg,
about 150
mg to about 1250 mg, about 150 mg to about 1000 mg, about 150 mg to about 750
mg, about
150 to about 500 mg, about 150 to about 300 mg, about 150 to about 200 mg, or
about 150,
155, 160, 165,170,175,180,185, 190, 195, 200,205,210,215,220,225,230,235,240,
245, 250, 255,260,265,270,275, 280, 285, 290,295,300,350,400, 450,500,
550,600,
650, 700, 750, 800, 850, 900,950, 1000, 1100,1200, 1300,1400, 1500,1600,
1700,1800,
1900, or 2000 mg is present in the composition. In some embodiments, up to
about 2000 mg,
up to about 1750 mg, up to about 1500 mg, up to about 1250 mg, up to about
1000 mg, up to
about 750 mg, up to about 500 mg of anti-TL1A is present in the composition.
The total
volume of the composition may be less than or equal to about 2 mL. The total
volume of the
composition may be less than or equal to about 2.5 mL. The total volume may be
less than
about or equal to about 9.0, 8.9, 8.8, 8.7,8.6, 8.5, 8.4, 8.3,8.2, 8.1, 8.0,
7.9,7.8, 7.7, 7.6, 7.5,
7.4, 7.3, 7.2, 7.1,7.0, 6.9, 6.8, 6.7,6.6, 6.5, 6.4, 6.3,6.2, 6.1, 6.0,
5.9,5.8, 5.7, 5.6, 5.5,5.4,
5.3, 5.2, 5.1, 5.0,4.9, 4.8, 4.7, 4.6,4.5, 4.4, 4.3, 4.2,4.1, 4, 3.9, 3.8,
3.7,3.6, 3.5, 3.4, 3.3,3.2,
3.1, 3.0, 2.9, 2.8,2.7, 2.6, 2.5, 2.4,2.3, 2.2, 2.1, 2.0,1.9, 1.8, 1.7,
1.6,1.5, 1.4, 1.3, 1.2,1.1,
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1.0, 0.9, or 0.8 mL. The total volume may be at least about 0.5 mL. The total
volume may be
about 0.5 mL to about 3 mL, about 0.5 mL to about 2.9 mL, about 0.5 mL to
about 2.8 mL,
about 0.5 mL to about 2.7 mL, about 0.5 mL to about 2.6 mL, about 0.5 mL to
about 2.5 mL,
about 0.5 mL to about 2.4 mL, about 0.5 mL to about 2.3 mL, about 0.5 mL to
about 2.2 mL,
about 0.5 mL to about 2.1 mL, about 0.5 mL to about 2 mL, 0.5 mL to about 1.9
mL, 0.5 mL
to about 1.8 mL, 0.5 mL to about 1.7 mL, 0.5 mL to about 1.6 mL, about 0.5 mL
to about 1.5
mL, about 0.5 mL to about 1.4 mL, about 0.5 mL to about 1.3 mL, about 0.5 mL
to about 1.2
mL, about 0.5 mL to about 1.1 mL, about 0.5 mL to about 1.0 mL, about 0.5 mL
to about 0.9
mL, about 0.5 mL to about 0.8 mL, about 0.6 mL to about 3 mL, about 0.6 mL to
about 2.9
mL, about 0.6 mL to about 2.8 mL, about 0.6 mL to about 2.7 mL, about 0.6 mL
to about 2.6
mL, about 0.6 mL to about 2.5 mL, about 0.6 mL to about 2.4 mL, about 0.6 mL
to about 2.3
mL, about 0.6 mL to about 2.2 mL, about 0.6 mL to about 2.1 mL, about 0.6 mL
to about 2.0
mL, about 0.6 mL to about 1.9 mL, about 0.6 mL to about 1.8 mL, about 0.6 mL
to about 1.7
mL, about 0.6 mL to about 1.6 mL, about 0.6 mL to about 1.5 mL, about 0.6 mL
to about 1.4
mL, about 0.6 mL to about 1.3 mL, about 0.6 mL to about 1.2 mL, about 0.6 mL
to about 1.1
mL, about 0.6 mL to about 1.0 mL, about 0.6 mL to about 0.9 mL, about 0.6 mL
to about U.S
mL, about 0.7 mL to about 3 mL, about 0.7 mL to about 2.9 mL, about 0.7 mL to
about 2.8
mL, about 0.7 mL to about 2.7 mL, about 0.7 mL to about 2.6 mL, about 0.7 mL
to about 2.5
mL, about 0.7 mL to about 2.4 mL, about 0.7 mL to about 2.3 mL, about 0.7 mL
to about 2.2
mL, about 0.7 mL to about 2.1 mL, about 0.7 mL to about 2.0 mL, about 0.7 mL
to about 1.9
mL, about 0.7 mL to about 1.8 mL, about 0.7 mL to about 1.7 mL, about 0.7 mL
to about 1.6
mL, about 0.7 mL to about 1.5 mL, about 0.7 mL to about 1.4 mL, about 0.7 mL
to about 1.3
mL, about 0.7 mL to about 1.2 mL, about 0.7 mL to about 1.1 mL, about 0.7 mL
to about 1.0
mL, about 0.7 mL to about 0.9 mL, about 0.7 mL to about 0.8 mL, about 3 mL to
about 10
mL, about 3 mL to about 9.5 mL, about 3 mL to about 9.0 mL, about 3 mL to
about 8.5 mL,
about 3 mL to about 8.0 mL, about 3 mL to about 7.5 mL, about 3 mL to about
7.0 mL, about
3 mL to about 6.5 mL, about 3 mL to about 6 mL, about 3 mL to about 5.5 mL,
about 3 mL
to about 5.0 mL, about 3 mL to about 4.5 mL, about 3 mL to about 4 mL, about 3
mL to
about 3.5 mL, about 3.5 mL to about 10 mL, about 3.5 mL to about 9.5 mL, about
3.5 mL to
about 9.0 mL, about 3.5 mL to about 8.5 mL, about 3.5 mL to about 8.0 mL,
about 3.5 mL to
about 7.5 mL, about 3.5 mL to about 7.0 mL, about 3.5 mL to about 6.5 mL,
about 3.5 mL to
about 6 mL, about 3.5 mL to about 5.5 mL, about 3.5 mL to about 5.0 mL, about
3.5 mL to
about 4.5 mL, about 3.5 mL to about 4 mL, about 4.0 mL to about 10 mL, about
4.0 mL to
about 9.5 mL, about 4.0 mL to about 9.0 mL, about 4.0 mL to about 8.5 mL,
about 4.0 mL to
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about 8.0 mL, about 4.0 mL to about 7.5 mL, about 4.0 mL to about 7.0 mL,
about 4.0 mL to
about 6.5 mL, about 4.0 mL to about 6 mL, about 4.0 mL to about 5.5 mL, about
4.0 mL to
about 5.0 mL, about 4.0 mL to about 4.5 mL, about 4.5 mL to about 10 mL, about
4.5 mL to
about 9.5 mL, about 4.5 mL to about 9.0 mL, about 4.5 mL to about 8.5 mL,
about 4.5 mL to
about 8.0 mL, about 4.5 mL to about 7.5 mL, about 4.5 mL to about 7.0 mL,
about 4.5 mL to
about 6.5 mL, about 4.5 mL to about 6 mL, about 4.5 mL to about 5.5 mL, about
4.5 mL to
about 5.0 mL, about 5 mL to about 10 mL, about 5 mL to about 9.5 mL, about 5
mL to about
9.0 mL, about 5 mL to about 8.5 mL, about 5 mL to about 8.0 mL, about 5 mL to
about 7.5
mL, about 5 mL to about 7.0 mL, about 5 mL to about 6.5 mL, about 5 mL to
about 6 mL,
about 5 mL to about 5.5 mL, about 5.5 mL to about 10 mL, about 5.5 mL to about
9.5 mL,
about 5.5 mL to about 9.0 mL, about 5.5 mL to about 8.5 mL, about 5.5 mL to
about 8.0 mL,
about 5.5 mL to about 7.5 mL, about 5.5 mL to about 7.0 mL, about 5.5 mL to
about 6.5 mL,
about 5.5 mL to about 6 mL, about 6.0 mL to about 10 mL, about 6.0 mL to about
9.5 mL,
about 6.0 mL to about 9.0 mL, about 6.0 mL to about 8.5 mL, about 6.0 mL to
about 8.0 mL,
about 6.0 mL to about 7.5 mL, about 6.0 mL to about 7.0 mL, about 6.0 mL to
about 6.5 mL,
about 6.5 mL to about 10 mL, about 6.5 mL to about 9.5 mL, about 6.5 mL to
about 9.0 mL,
about 6.5 mL to about 8.5 mL, about 6.5 mL to about 8.0 mL, about 6.5 mL to
about 7.5 mL,
about 6.5 mL to about 7.0 mL, about 7.0 mL to about 10 mL, about 7.0 mL to
about 9.5 mL,
about 7.0 mL to about 9.0 mL, about 7.0 mL to about 8.5 mL, about 7.0 mL to
about 8.0 mL,
about 7.0 mL to about 7.5 mL, about 7.5 mL to about 10 mL, about 7.5 mL to
about 9.5 mL,
about 7.5 mL to about 9.0 mL, about 7.5 mL to about 8.5 mL, about 7.5 mL to
about 8.0 mL,
about 8.0 mL to about 10 mL, about 8.0 mL to about 9.5 mL, about 8.0 mL to
about 9.0 mL,
about 8.0 mL to about 8.5 mL, about 8.5 mL to about 10 mL, about 8.5 mL to
about 9.5 mL,
about 8.5 mL to about 9.0 mL, about 9 mL to about 10 mL, about 9 mL to about
9.5 mL, or
about 9.5 mL to about 10 mL. The composition may have a viscosity of less than
or about 20
centipoise (cP). The composition may have a viscosity of less than or about 15
centipoise
(cP). The composition may have a viscosity of less than or about 10 centipoise
(cP). For
instance, the composition has a viscosity ofless than or about 20, 19, 18, 17,
16, 15, 14, 13,
12, 11, 10, 9, 8, 7,6, 5, 4, 3, or 2 cP. The composition may have a viscosity
of at least about
1, 2 or 3 cP. Further example viscosities include about 1 cP to about 2 cP,
about 1 cP to about
3 cP, about 1 cP to about 4 cP, about 1 cP to about 5 cP, about 1 cP to about
6 cP, about 1 cP
to about 7 cP, about 1 cP to about 8 cP, about 1 cP to about 9 cP, about 1 cP
to about 10 cP,
about 1 cP to about 11 cP, about 1 cP to about 12 cP, about 1 cP to about 13
cP, about 1 cP to
about 14 cP, about 1 cP to about 15 cP, about 1 cP to about 16 cP, about 1 cP
to about 17 cP,
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about 1 cP to about 18 cP, about 1 cP to about 19 cP, about 1 cP to about 20
cP, about 2 cP to
about 5 cP, about 2 cP to about 6 cP, about 2 cP to about 7 cP, about 2 cP to
about 8 cP, about
2 cP to about 9 cP, about 2 cP to about 10 cP, about 2 cP to about 11 cP,
about 2 cP to about
12 cP, about 2 cP to about 13 cP, about 2 cP to about 14 cP, about 2 cP to
about 15 cP, about
2 cP to about 16 cP, about 2 cP to about 17 cP, about 2 cP to about 18 cP,
about 2 cP to about
19 cP, about 2 cP to about 20 cP, about 3 cP to about 5 cP, about 3 cP to
about 6 cP, about 3
cP to about 7 cP, about 3 cP to about 8 cP, about 3 cP to about 9 cP, about 3
cP to about 10
cP, about 3 cP to about 11 cP, about 3 cP to about 12 cP, about 3 cP to about
13 cP, about 3
cP to about 14 cP, about 3 cP to about 15 cP, about 3 cP to about 16 cP, about
3 cP to about
17 cP, about 3 cP to about 18 cP, about 3 cP to about 19 cP, about cP to about
20 cP, about 4
cP to about 5 cP, about 4 cP to about 6 cP, about 4 cP to about 7 cP, about 4
cP to about 8 cP,
about 4 cP to about 9 cP, about 4 cP to about 10 cP. about 4 cP to about 11
cP, about 4 cP to
about 12 cP, about 4 cP to about 13 cP, about 4 cP to about 14 cP, about 4 cP
to about 15 cP,
about 4 cP to about 16 cP, about 4 cP to about 17 cP, about 4 cP to about 18
cP, about 4 cP to
about 19 cP, about 4 cP to about 20 cP, about 5 cP to about 10 cP, about 5 cP
to about 11 cP,
about 5 cP to about 12 cP, about 5 cP to about 13 cP, about 5 cP to about 14
cP, about 5 cP to
about 15 cP, about 5 cP to about 16 cP, about 5 cP to about 17 cP, about 5 cP
to about 18 cP,
about 5 cP to about 19 cP, about 5 cP to about 20 cP, about 6 cP to about 10
cP, about 6 cP to
about 11 cP, about 6 cP to about 12 cP, about 6 cP to about 13 cP, about 6 cP
to about 14 cP,
about 6 cP to about 15 cP, about 6 cP to about 16 cP, about 6 cP to about 17
cP, about 6 cP to
about 18 cP, about 6 cP to about 19 cP, about 6 cP to about 20 cP, about 7 cP
to about 10 cP,
about 7 cP to about 11 cP, about 7 cP to about 12 cP, about 7 cP to about 13
cP, about 7 cP to
about 14 cP, about 7 cP to about 15 cP, about 7 cP to about 16 cP, about 7 cP
to about 17 cP,
about 7 cP to about 18 cP, about 7 cP to about 19 cP, about 7 cP to about 20
cP, about 8 cP to
about 10 cP, about 8 cP to about 11 cP, about 8 cP to about 12 cP, about 8 cP
to about 13 cP,
about 8 cP to about 14 cP, about 8 cP to about 15 cP, about 8 cP to about 16
cP, about 8 cP to
about 17 cP, about 8 cP to about 18 cP, about 8 cP to about 19 cP, or about 8
cP to about 20
cP. In some embodiments, the concentration of anti-TL1A is about or greater
than about 55,
60, 65, 70, 75, 80, 85,90, 95, 100,105,110,115,120,125,130, 135,140, 145,
155,160,
165, 170, 175, 180, 185, 190,195, 200, 205, 210,215,220,225,230,235,240,245,
or 250
mg/mL.
1002761 In certain embodiments, provided herein is a pharmaceutical
composition
comprising a therapeutically effective dose of an anti-TL1A antibody, wherein
the
pharmaceutical composition has a viscosity of less than about 20 cP, 15 cP, or
10 cP. The
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composition may have a viscosity of less than or about 20 cP. The composition
may have a
viscosity of less than or about 15 cP. The composition may have a viscosity of
less than or
about 10 cP. For instance, the composition has a viscosity of less than or
about 20, 19, 18, 17,
16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2 cP. The composition may
have a viscosity of
at least about 1, 2 or 3 cP. Further example viscosities include about 1 cP to
about 2 cP, about
1 cP to about 3 cP, about 1 cP to about 4 cP, about 1 cP to about 5 cP, about
1 cP to about 6
cP, about 1 cP to about 7 cP, about 1 cP to about 8 cP, about 1 cP to about 9
cP, about 1 cP to
about 10 cP, about 1 cP to about 11 cP, about 1 cP to about 12 cP, about 1 cP
to about 13 cP,
about 1 cP to about 14 cP, about 1 cP to about 15 cP, about 1 cP to about 16
cP, about 1 cP to
about 17 cP, about 1 cP to about 18 cP, about 1 cP to about 19 cP, about 1 cP
to about 20 cP,
about 2 cP to about 5 cP, about 2 cP to about 6 cP, about 2 cP to about 7 cP,
about 2 cP to
about 8 cP, about 2 cP to about 9 cP, about 2 cP to about 10 cP, about 2 cP to
about 11 cP,
about 2 cP to about 12 cP, about 2 cP to about 13 cP, about 2 cP to about 14
cP, about 2 cP to
about 15 cP, about 2 cP to about 16 cP, about 2 cP to about 17 cP, about 2 cP
to about 18 cP,
about 2 cP to about 19 cP, about 2 cP to about 20 cP, about 3 cP to about 5
cP, about 3 cP to
about 6 cP, about 3 cP to about 7 cP, about 3 cP to about 8 cP, about 3 cP to
about 9 cP, about
3 cP to about 10 cP, about 3 cP to about 11 cP, about 3 cP to about 12 cP,
about 3 cP to about
13 cP, about 3 cP to about 14 cP, about 3 cP to about 15 cP, about 3 cP to
about 16 cP, about
3 cP to about 17 cP, about 3 cP to about 18 cP, about 3 cP to about 19 cP,
about cP to about
20 cP, about 4 cP to about 5 cP, about 4 cP to about 6 cP, about 4 cP to about
7 cP, about 4
cP to about 8 cP, about 4 cP to about 9 cP, about 4 cP to about 10 cP. about 4
cP to about 11
cP, about 4 cP to about 12 cP, about 4 cP to about 13 cP, about 4 cP to about
14 cP, about 4
cP to about 15 cP, about 4 cP to about 16 cP, about 4 cP to about 17 cP, about
4 cP to about
18 cP, about 4 cP to about 19 cP, about 4 cP to about 20 cP, about 5 cP to
about 10 cP, about
cP to about 11 cP, about 5 cP to about 12 cP, about 5 cP to about 13 cP, about
5 cP to about
14 cP, about 5 cP to about 15 cP, about 5 cP to about 16 cP, about 5 cP to
about 17 cP, about
5 cP to about 18 cP, about 5 cP to about 19 cP, about 5 cP to about 20 cP,
about 6 cP to about
cP, about 6 cP to about 11 cP, about 6 cP to about 12 cP, about 6 cP to about
13 cP, about
6 cP to about 14 cP, about 6 cP to about 15 cP, about 6 cP to about 16 cP, ab
out 6 cP to about
17 cP, about 6 cP to about 18 cP, about 6 cP to about 19 cP, about 6 cP to
about 20 cP, about
7 cP to about 10 cP, about 7 cP to about 11 cP, about 7 cP to about 12 cP,
about 7 cP to about
13 cP, about 7 cP to about 14 cP, about 7 cP to about 15 cP, about 7 cP to
about 16 cP, about
7 cP to about 17 cP, about 7 cP to about 18 cP, about 7 cP to about 19 cP,
about 7 cP to about
cP, about 8 cP to about 10 cP, about 8 cP to about 11 cP, about 8 cP to about
12 cP, about
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8 cP to about 13 cP, about 8 cP to about 14 cP, about 8 cP to about 15 cP,
about 8 cP to about
16 cP, about 8 cP to about 17 cP, about 8 cP to about 18 cP, about 8 cP to
about 19 cP, or
about 8 cP to about 20 cP. In some embodiments, the therapeutically effective
dose is at least
about 150 mg anti-TL1A antibody. In some cases, the therapeutically effective
dose is about
rat least about 150, 155, 160, 165, 170, 175, 180, 185, 190, 195,200, 205,210,
215,220,
225, 230, 235,240,245,250,255, 260, 265, 270,275,280,285,290,295,300,350,400,
450, 500, 550, 600, 650, 700,750, 800, 850, 900, 950, 1000, 1100, 1200, 1300,
1400, 1500,
1600, 1700, 1800, 1900, or 2000 mg of anti-TL1A. In some cases, the
therapeutically
effective dose is about 150 mg to about 2000 mg, about 150 mg to about 1750
mg, about 150
mg to about 1500 mg, about 150 mg to about 1250 mg, about 150 mg to about 1000
mg,
about 150 mg to about 750 mg, about 150 mg to about 500 mg, about 150 mg to
about 450
mg, about 150 mg to about 400 mg, about 150 mg to about 350 mg, about 150 mg
to about
300 mg, about 150 mg to about 250 mg, or about 150 mg to about 200 mg anti-
TL1A. The
total volume of the composition may be less than or equal to about 2 mL. The
total volume of
the composition may be less than or equal to about 2.5 mL. The total volume
may be less
than about or equal to about 9.0, 8.9, 8.8, 8.7, 8.6, 8.5, 8.4, 8.3, 8.2, 8.1,
8.0, 7.9, 7.8, 7.7, 7.6,
7.5, 7.4, 7.3, 7.2,7.1, 7.0, 6.9, 6.8,6.7, 6.6, 6.5, 6.4,6.3, 6.2, 6.1,
6.0,5.9, 5.8, 5.7, 5.6,5.5,
5.4, 5.3, 5.2, 5.1,5.0, 4.9, 4.8, 4.7,4.6, 4.5, 4.4, 4.3,4.2, 4.1, 4, 3.9,
3.8,3.7, 3.6, 3.5, 3.4,3.3,
3.2, 3.1, 3.0, 2.9,2.8, 2.7, 2.6, 2.5,2.4, 2.3, 2.2, 2.1,2.0, 1.9, 1.8,
1.7,1.6, 1.5, 1.4, 1.3,1.2,
1.1, 1.0, 0.9, or 0.8 mL. The total volume may be at least about 0.5 mL. The
total volume
may be about 0.5 mL to about 3 mL, about 0.5 mL to about 2.9 mL, about 0.5 mL
to about
2.8 mL, about 0.5 mL to about 2.7 mL, about 0.5 mL to about 2.6 mL, about 0.5
mL to about
2.5 mL, about 0.5 mL to about 2.4 mL, about 0.5 mL to about 2.3 mL, about 0.5
mL to about
2.2 mL, about 0.5 mL to about 2.1 mL, about 0.5 mL to about 2 mL, 0.5 mL to
about 1.9 mL,
0.5 mL to about 1.8 mL, 0.5 mL to about 1.7 mL, 0.5 mL to about 1.6 mL, about
0.5 mL to
about 1.5 mL, about 0.5 mL to about 1.4 mL, about 0.5 mL to about 1.3 mL,
about 0.5 mL to
about 1.2 mL, about 0.5 mL to about 1.1 mL, about 0.5 mL to about 1.0 mL,
about 0.5 mL to
about 0.9 mL, about 0.5 mL to about 0.8 mL, about 0.6 mL to about 3 mL, about
0.6 mL to
about 2.9 mL, about 0.6 mL to about 2.8 mL, about 0.6 mL to about 2.7 mL,
about 0.6 mL to
about 2.6 mL, about 0.6 mL to about 2.5 mL, about 0.6 mL to about 2.4 mL,
about 0.6 mL to
about 2.3 mL, about 0.6 mL to about 2.2 mL, about 0.6 mL to about 2.1 mL,
about 0.6 mL to
about 2.0 mL, about 0.6 mL to about 1.9 mL, about 0.6 mL to about 1.8 mL,
about 0.6 mL to
about 1.7 mL, about 0.6 mL to about 1.6 mL, about 0.6 mL to about 1.5 mL,
about 0.6 mL to
about 1.4 mL, about 0.6 mL to about 1.3 mL, about 0.6 mL to about 1.2 mL,
about 0.6 mL to
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about 1.1 mL, about 0.6 mL to about 1.0 mL, about 0.6 mL to about 0.9 mL,
about 0.6 mL to
about 0.8 mL, about 0.7 mL to about 3 mL, about 0.7 mL to about 2.9 mL, about
0.7 mL to
about 2.8 mL, about 0.7 mL to about 2.7 mL, about 0.7 mL to about 2.6 mL,
about 0.7 mL to
about 2.5 mL, about 0.7 mL to about 2.4 mL, about 0.7 mL to about 2.3 mL,
about 0.7 mL to
about 2.2 mL, about 0.7 mL to about 2.1 mL, about 0.7 mL to about 2.0 mL,
about 0.7 mL to
about 1.9 mL, about 0.7 mL to about 1.8 mL, about 0.7 mL to about 1.7 mL,
about 0.7 mL to
about 1.6 mL, about 0.7 mL to about 1.5 mL, about 0.7 mL to about 1.4 mL,
about 0.7 mL to
about 1.3 mL, about 0.7 mL to about 1.2 mL, about 0.7 mL to about 1.1 mL,
about 0.7 mL to
about 1.0 mL, about 0.7 mL to about 0.9 mL, about 0.7 mL to about 0.8 mL,
about 3 mL to
about 10 mL, about 3 mL to about 9.5 mL, about 3 mL to about 9.0 mL, about 3
mL to about
8.5 mL, about 3 mL to about 8.0 mL, about 3 mL to about 7.5 mL, about 3 mL to
about 7.0
mL, about 3 mL to about 6.5 mL, about 3 mL to about 6 mL, about 3 mL to about
5.5 mL,
about 3 mL to about 5.0 mL, about 3 mL to about 4.5 mL, about 3 mL to about 4
mL, about 3
mL to about 3.5 mL, about 3.5 mL to about 10 mL, about 3.5 mL to about 9.5 mL,
about 3.5
mL to about 9.0 mL, about 3.5 mL to about 8.5 mL, about 3.5 mL to about 8.0
mL, about 3.5
mL to about 7.5 mL, about 3.5 mL to about 7.0 mL, about 3 .5 mL to about 6.5
mL, about 3.5
mL to about 6 mL, about 3.5 mL to about 5.5 mL, about 3.5 mL to about 5.0 mL,
about 3.5
mL to about 4.5 mL, about 3.5 mL to about 4 mL, about 4.0 mL to about 10 mL,
about 4.0
mL to about 9.5 mL, about 4.0 mL to about 9.0 mL, about 4.0 mL to about 8.5
mL, about 4.0
mL to about 8.0 mL, about 4.0 mL to about 7.5 mL, about 4.0 mL to about 7.0
mL, about 4.0
mL to about 6.5 mL, about 4.0 mL to about 6 mL, about 4.0 mL to about 5.5 mL,
about 4.0
mL to about 5.0 mL, about 4.0 mL to about 4.5 mL, about 4.5 mL to about 10 mL,
about 4.5
mL to about 9.5 mL, about 4.5 mL to about 9.0 mL, about 4.5 mL to about 8.5
mL, about 4.5
mL to about 8.0 mL, about 4.5 mL to about 7.5 mL, about 4.5 mL to about 7.0
mL, about 4.5
mL to about 6.5 mL, about 4.5 mL to about 6 mL, about 4.5 mL to about 5.5 mL,
about 4.5
mL to about 5.0 mL, about 5 mL to about 10 mL, about 5 mL to about 9.5 mL,
about 5 mL to
about 9.0 mL, about 5 mL to about 8.5 mL, about 5 mL to about 8.0 mL, about 5
mL to about
7.5 mL, about 5 mL to about 7.0 mL, about 5 mL to about 6.5 mL, about 5 mL to
about 6
mL, about 5 mL to about 5.5 mL, about 5.5 mL to about 10 mL, about 5.5 mL to
about 9.5
mL, about 5.5 mL to about 9.0 mL, about 5.5 mL to about 8.5 mL, about 5.5 mL
to about 8.0
mL, about 5.5 mL to about 7.5 mL, about 5.5 mL to about 7.0 mL, about 5.5 mL
to about 6.5
mL, about 5.5 mL to about 6 mL, about 6.0 mL to about 10 mL, about 6.0 mL to
about 9.5
mL, about 6.0 mL to about 9.0 mL, about 6.0 mL to about 8.5 mL, about 6.0 mL
to about 8.0
mL, about 6.0 mL to about 7.5 mL, about 6.0 mL to about 7.0 mL, about 6.0 mL
to about 6.5
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mL, about 6.5 mL to about 10 mL, about 6.5 mL to about 9.5 mL, about 6.5 mL to
about 9.0
mL, about 6.5 mL to about 8.5 mL, about 6.5 mL to about 8.0 mL, about 6.5 mL
to about 7.5
mL, about 6.5 mL to about 7.0 mL, about 7.0 mL to about 10 mL, about 7.0 mL to
about 9.5
mL, about 7.0 mL to about 9.0 mL, about 7.0 mL to about 8.5 mL, about 7.0 mL
to about 8.0
mL, about 7.0 mL to about 7.5 mL, about 7.5 mL to about 10 mL, about 7.5 mL to
about 9.5
mL, about 7.5 mL to about 9.0 mL, about 7.5 mL to about 8.5 mL, about 7.5 mL
to about 8.0
mL, about 8.0 mL to about 10 mL, about 8.0 mL to about 9.5 mL, about 8.0 mL to
about 9.0
mL, about 8.0 mL to about 8.5 mL, about 8.5 mL to about 10 mL, about 8.5 mL to
about 9.5
mL, about 8.5 mL to about 9.0 mL, about 9 mL to about 10 mL, about 9 mL to
about 9.5 mL,
or about 9.5 mL to about 10 mL. In some embodiments, the concentration of anti-
TL1A is
about or greater than about 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110,
115, 120, 125,
130, 135, 140,145, 155, 160, 165, 170,175,180,185, 190, 195, 200, 205,
210,215,220,
225, 230,235,240,245, or 250 mg/mL.
1002771 In certain embodiments, provided herein is a pharmaceutical
composition
comprising a therapeutically effective dose of an anti-TL1A antibody having a
percentage
aggregation of the anti-TL1A antibody as measured by size exclusion
chromatography ofless
than about 5% of the total anti-TL1A antibody in the composition. In some
embodiments, the
percentage aggregation of anti-TL1A antibody as measured by size exclusion
chromatography is less than about 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%,
0.9%, 0.8%,
0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1% of the composition volume. In some
embodiments, the therapeutically effective dose is at least about 150 mg anti-
TL1A antibody.
In some cases, the therapeutically effective dose is about or at least about
150, 155, 160, 165,
170, 175, 180,185,190,195,200,205,210, 215, 220, 225,230,235,240,245,250,255,
260, 265, 270,275,280, 285, 290, 295,300,350, 400, 450, 500, 550, 600, 650,
700, 750,
800, 850, 900, 950, 1000, 1100,1200, 1300, 1400, 1500,1600, 1700,1800, 1900,
or 2000 mg
of anti-TL1A. In some cases, the therapeutically effective dose is about 150
mg to about 2000
mg, about 150 mg to about 1750 mg, about 150 mg to about 1500 mg, about 150 mg
to about
1250 mg, about 150 mg to about 1000 mg, about 150 mg to about 750 mg, about
150 mg to
about 500 mg, about 150 mg to about 450 mg, about 150 mg to about 400 mg,
about 150 mg
to about 350 mg, about 150 mg to about 300 mg, about 150 mg to about 250 mg,
or about
150 mg to about 200 mg anti-TL1A. The total volume of the composition may be
less than or
equal to about 2 mL. The total volume of the composition may be less than or
equal to about
2.5 mL. The total volume may be less than about or equal to about 9.0, 8.9,
8.8, 8.7, 8.6, 8.5,
8.4, 8.3, 8.2, 8.1,8.0, 7.9, 7.8, 7.7,7.6, 7.5, 7.4, 7.3,7.2, 7.1, 7.0,
6.9,6.8, 6.7, 6.6, 6.5,6.4,
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6.3, 6.2, 6.1, 6.0, 5.9, 5.8, 5.7, 5.6, 5.5, 5.4, 5.3, 5.2, 5.1, 5.0, 4.9,
4.8,4.7, 4.6, 4.5, 4.4,4.3,
4.2, 4.1, 4, 3.9, 3.8,3.7, 3.6, 3.5, 3.4,3.3, 3.2, 3.1, 3.0,2.9, 2.8, 2.7,
2.6,2.5, 2.4, 2.3, 2.2,2.1,
2.0, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.9, or 0.8 mL. The
total volume maybe at
least about 0.5 mL. The total volume may be about 0.5 mL to about 3 mL, about
0.5 mL to
about 2.9 mL, about 0.5 mL to about 2.8 mL, about 0.5 mL to about 2.7 mL,
about 0.5 mL to
about 2.6 mL, about 0.5 mL to about 2.5 mL, about 0.5 mL to about 2.4 mL,
about 0.5 mL to
about 2.3 mL, about 0.5 mL to about 2.2 mL, about 0.5 mL to about 2.1 mL,
about 0.5 mL to
about 2 mL, 0.5 mL to about 1.9 mL, 0.5 mL to about 1.8 mL, 0.5 mL to about
1.7 mL, 0.5
mL to about 1.6 mL, about 0.5 mL to about 1.5 mL, about 0.5 mL to about 1.4
mL, about 0.5
mL to about 1.3 mL, about 0.5 mL to about 1.2 mL, about 0.5 mL to about 1.1
mL, about 0.5
mL to about 1.0 mL, about 0.5 mL to about 0.9 mL, about 0.5 mL to about 0.8
mL, about 0.6
mL to about 3 mL, about 0.6 mL to about 2.9 mL, about 0.6 mL to about 2.8 mL,
about 0.6
mL to about 2.7 mL, about 0.6 mL to about 2.6 mL, about 0.6 mL to about 2.5
mL, about 0.6
mL to about 2.4 mL, about 0.6 mL to about 2.3 mL, about 0.6 mL to about 2.2
mL, about 0.6
mL to about 2.1 mL, about 0.6 mL to about 2.0 mL, about 0.6 mL to about 1.9
mL, about 0.6
mL to about 1.8 mL, about 0.6 mL to about 1 .7 mL, about 0.6 mL to about 1.6
mL, about 0.6
mL to about 1.5 mL, about 0.6 mL to about 1.4 mL, about 0.6 mL to about 1.3
mL, about 0.6
mL to about 1.2 mL, about 0.6 mL to about 1.1 mL, about 0.6 mL to about 1.0
mL, about 0.6
mL to about 0.9 mL, about 0.6 mL to about 0.8 mL, about 0.7 mL to about 3 mL,
about 0.7
mL to about 2.9 mL, about 0.7 mL to about 2.8 mL, about 0.7 mL to about 2.7
mL, about 0.7
mL to about 2.6 mL, about 0.7 mL to about 2.5 mL, about 0.7 mL to about 2.4
mL, about 0.7
mL to about 2.3 mL, about 0.7 mL to about 2.2 mL, about 0.7 mL to about 2.1
mL, about 0.7
mL to about 2.0 mL, about 0.7 mL to about 1.9 mL, about 0.7 mL to about 1.8
mL, about 0.7
mL to about 1.7 mL, about 0.7 mL to about 1 .6 mL, about 0.7 mL to about 1 .5
mL, about 0.7
mL to about 1.4 mL, about 0.7 mL to about 1.3 mL, about 0.7 mL to about 1.2
mL, about 0.7
mL to about 1.1 mL, about 0.7 mL to about 1.0 mL, about 0.7 mL to about 0.9
mL, about 0.7
mL to about 0.8 mL, about 3 mL to about 10 mL, about 3 mL to about 9.5 mL,
about 3 mL to
about 9.0 mL, about 3 mL to about 8.5 mL, about 3 mL to about 8.0 mL, about 3
mL to about
7.5 mL, about 3 mL to about 7.0 mL, about 3 mL to about 6.5 mL, about 3 mL to
about 6
mL, about 3 mL to about 5.5 mL, about 3 mL to about 5.0 mL, about 3 mL to
about 4.5 mL,
about 3 mL to about 4 mL, about 3 mL to about 3.5 mL, about 3.5 mL to about 10
mL, about
3.5 mL to about 9.5 mL, about 3.5 mL to about 9.0 mL, about 3.5 mL to about
8.5 mL, about
3.5 mL to about 8.0 mL, about 3.5 mL to about 7.5 mL, about 3.5 mL to about
7.0 mL, about
3.5 mL to about 6.5 mL, about 3.5 mL to about 6 mL, about 3.5 mL to about 5.5
mL, about
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3.5 mL to about 5.0 mL, about 3.5 mL to about 4.5 mL, about 3.5 mL to about 4
mL, about
4.0 mL to about 10 mL, about 4.0 mL to about 9.5 mL, about 4.0 mL to about 9.0
mL, about
4.0 mL to about 8.5 mL, about 4.0 mL to about 8.0 mL, about 4.0 mL to about
7.5 mL, about
4.0 mL to about 7.0 mL, about 4.0 mL to about 6.5 mL, about 4.0 mL to about 6
mL, about
4.0 mL to about 5.5 mL, about 4.0 mL to about 5.0 mL, about 4.0 mL to about
4.5 mL, about
4.5 mL to about 10 mL, about 4.5 mL to about 9.5 mL, about 4.5 mL to about 9.0
mL, about
4.5 mL to about 8.5 mL, about 4.5 mL to about 8.0 mL, about 4.5 mL to about
7.5 mL, about
4.5 mL to about 7.0 mL, about 4.5 mL to about 6.5 mL, about 4.5 mL to about 6
mL, about
4.5 mL to about 5.5 mL, about 4.5 mL to about 5.0 mL, about 5 mL to about 10
mL, about 5
mL to about 9.5 mL, about 5 mL to about 9.0 mL, about 5 mL to about 8.5 mL,
about 5 mL
to about 8.0 mL, about 5 mL to about 7.5 mL, about 5 mL to about 7.0 mL, about
5 mL to
about 6.5 mL, about 5 mL to about 6 mL, about 5 mL to about 5.5 mL, about 5.5
mL to about
mL, about 5.5 mL to about 9.5 mL, about 5.5 mL to about 9.0 mL, about 5.5 mL
to about
8.5 mL, about 5.5 mL to about 8.0 mL, about 5.5 mL to about 7.5 mL, about 5.5
mL to about
7.0 mL, about 5.5 mL to about 6.5 mL, about 5.5 mL to about 6 mL, about 6.0 mL
to about
10 mL, about 6.0 mL to about 9.5 mL, about 6.0 mL to about 9.0 mL, about 6.0
mL to about
8.5 mL, about 6.0 mL to about 8.0 mL, about 6.0 mL to about 7.5 mL, about 6.0
mL to about
7.0 mL, about 6.0 mL to about 6.5 mL, about 6.5 mL to about 10 mL, about 6.5
mL to about
9.5 mL, about 6.5 mL to about 9.0 mL, about 6.5 mL to about 8.5 mL, about 6.5
mL to about
8.0 mL, about 6.5 mL to about 7.5 mL, about 6.5 mL to about 7.0 mL, about 7.0
mL to about
10 mL, about 7.0 mL to about 9.5 mL, about 7.0 mL to about 9.0 mL, about 7.0
mL to about
8.5 mL, about 7.0 mL to about 8.0 mL, about 7.0 mL to about 7.5 mL, about 7.5
mL to about
10 mL, about 7.5 mL to about 9.5 mL, about 7.5 mL to about 9.0 mL, about 7.5
mL to about
8.5 mL, about 7.5 mL to about 8.0 mL, about 8.0 mL to about 10 mL, about 8.0
mL to about
9.5 mL, about 8.0 mL to about 9.0 mL, about 8.0 mL to about 8.5 mL, about 8.5
mL to about
10 mL, about 8.5 mL to about 9.5 mL, about 8.5 mL to about 9.0 mL, about 9 mL
to about 10
mL, about 9 mL to about 9.5 mL, or about 9.5 mL to about 10 mL. In some
embodiments, the
concentration of anti-TL1A is about or greater than about 55, 60, 65, 70, 75,
80, 85, 90, 95,
100, 105, 110,115,120,125,130,135,140,145, 155,160,165,170,175,180,185,190,
195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, or 250 mg/mL.
1002781 In certain embodiments, the pharmaceutical composition has a volume
suitable for
injection, such as via subcutaneous administration. In some embodiments, the
total volume of
the composition may be less than or equal to about 2.5 mL. In some
embodiments, the total
volume of the composition is less than about 2 mL, less than about or equal to
about 9.0, 8.9,
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8.8, 8.7, 8.6, 8.5,8.4, 8.3, 8.2, 8.1,8.0, 7.9, 7.8, 7.7,7.6, 7.5, 7.4,
7.3,7.2, 7.1, 7.0, 6.9,6.8,
6.7, 6.6, 6.5, 6.4,6.3, 6.2, 6.1, 6.0,5.9, 5.8, 5.7, 5.6, 5.5, 5.4, 5.3,
5.2,5.1, 5.0, 4.9, 4.8,4.7,
4.6, 4.5, 4.4, 4.3,4.2, 4.1, 4, 3.9, 3.8,3.7, 3.6, 3.5, 3.4,3.3, 3.2, 3.1,
3.0,2.9, 2.8, 2.7, 2.6,2.5,
2.4, 2.3, 2.2, 2.1,2.0, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.9,
or 0.8 mL. Antibody
therapeutics suitable for injection and/or administration are important to
realizing full
therapeutic potential. However, administration is generally restricted by
volume, for instance,
when the therapeutic is delivered subcutaneously. This, in turn, elucidates
the importance
developing of high concentration antibody formulations of greater than, for
example in some
cases, 100 mg/ml. Problems associated with antibody development include high
solution
viscosity and opalescence, which are commonly encountered during the
development of high-
concentration (e.g., greater than 100 mg/ml). Both viscosity and opalescence
impact antibody
developability broadly, affecting manufacturability, stability, and delivery.
High solution
viscosities (e.g., greater than 30 mPa-s) cause limiting back-pressures in
ultrafiltration/diafiltration during the antibody concentration unit
operation. Similarly,
viscous antibody solutions also result in forbidding or incompatible injection
forces when
administering via injection, including via patient friendly autoinjectors. In
effect, solution
viscosity can be a determining factor for the maximum antibody dose possible
via injection.
Solution opalescence in therapeutic antibodies can be equally problematic as
opalescence can
indicate predisposition for liquid-liquid phase separation, precipitation, or
aggregation.
Further difficulty may occur with blinding of subcutaneous placebo.
1002791 The anti-TL1A antibodies provided herein demonstrate advantageous
viscosity
and aggregation properties at high antibody concentrations (e.g., greater than
about 100, 125,
150, 160, 170, 180, 190, or 200 mg/mL). Notably, anti-TL1A antibodies provided
herein are
characterized by low viscosity (e.g., less than 20 mPa-s) and low aggregation
(e.g., less than
5% high molecular weight species) at high concentrations (FIGS. 3A-3C).
1002801 For example, in some embodiments, the anti-T1LA antibody is
characterized by a
viscosity less than about 30, 20, 15, or 10 mPa-s at a concentration greater
than about 100
mg/mL, e.g., about 150 mg/mL to about 300 mg/mL, about 150 mg/mL to about 200
mg/mL,
about 150 mg/mL to about 225 mg/mL, or about 150 mg/mL to about 250 mg/mL. In
some
cases, the antibody comprises a HCDR1 comprising SEQ ID NO: 1, a HCDR2
comprising
SEQ ID NO: 2, a HCDR3 comprising SEQ ID NO: 6, a LCDR1 comprising SEQ ID NO:
10,
a LCDR2 comprising SEQ ID NO: 11, and a LCDR3 comprising SEQ ID NO: 12, and/or
having a heavy chain variable region comprising SEQ ID NO: 104 and a light
chain variable
region comprising SEQ ID NO: 201. In some cases, the anti-TL1A antibody
comprises a
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human IGHV1-46*02 framework or a modified human IGHV1-46*02 framework, and a
light
chain variable framework region comprising a human IGKV3 -20 framework or a
modified
human IGKV3 -20 framework; wherein the heavy chain variable framework region
and the
light chain variable framework region collectively comprise less than 9 amino
acid
modifications from the human IGHV1-46*02 framework and the human IGKV3 -20
framework. For instance, the composition has a viscosity of less than or about
20, 19, 18, 17,
16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2 cP. The composition may
have a viscosity of
at least about 1, 2 or 3 cP. Further example viscosities include about 1 cP to
about 5 cP, about
1 cP to about 6 cP, about 1 cP to about 7 cP, about 1 cP to about 8 cP, about
1 cP to about 9
cP, about 1 cP to about 10 cP, about 1 cP to about 11 cP, about 1 cP to about
12 cP, about 1
cP to about 13 cP, about 1 cP to about 14 cP, about 1 cP to about 15 cP, about
1 cP to about
16 cP, about 1 cP to about 17 cP, about 1 cP to about 18 cP, about 1 cP to
about 19 cP, about
1 cP to about 20 cP, about 2 cP to about 5 cP, about 2 cP to about 6 cP, about
2 cP to about 7
cP, about 2 cP to about 8 cP, about 2 cP to about 9 cP, about 2 cP to about 10
cP, about 2 cP
to about 11 cP, about 2 cP to about 12 cP, about 2 cP to about 13 cP, about 2
cP to about 14
cP, about 2 cP to about 15 cP, about 2 cP to about 16 cP, about 2 cP to about
17 cP, about 2
cP to about 18 cP, about 2 cP to about 19 cP, about 2 cP to about 20 cP, about
3 cP to about 5
cP, about 3 cP to about 6 cP, about 3 cP to about 7 cP, about 3 cP to about 8
cP, about 3 cP to
about 9 cP, about 3 cP to about 10 cP, about 3 cP to about 11 cP, about 3 cP
to about 12 cP,
about 3 cP to about 13 cP, about 3 cP to about 14 cP, about 3 cP to about 15
cP, about 3 cP to
about 16 cP, about 3 cP to about 17 cP, about 3 cP to about 18 cP, about 3 cP
to about 19 cP,
about cP to about 20 cP, about 4 cP to about 5 cP, about 4 cP to about 6 cP,
about 4 cP to
about 7 cP, about 4 cP to about 8 cP, about 4 cP to about 9 cP, about 4 cP to
about 10 cP.
about 4 cP to about 11 cP, about 4 cP to about 12 cP, about 4 cP to about 13
cP, about 4 cP to
about 14 cP, about 4 cP to about 15 cP, about 4 cP to about 16 cP, about 4 cP
to about 17 cP,
about 4 cP to about 18 cP, about 4 cP to about 19 cP, about 4 cP to about 20
cP, about 5 cP to
about 10 cP, about 5 cP to about 11 cP, about 5 cP to about 12 cP, about 5 cP
to about 13 cP,
about 5 cP to about 14 cP, about 5 cP to about 15 cP, about 5 cP to about 16
cP, about 5 cP to
about 17 cP, about 5 cP to about 18 cP, about 5 cP to about 19 cP, about 5 cP
to about 20 cP,
about 6 cP to about 10 cP, about 6 cP to about 11 cP, about 6 cP to about 12
cP, about 6 cP to
about 13 cP, about 6 cP to about 14 cP, about 6 cP to about 15 cP, about 6 cP
to about 16 cP,
about 6 cP to about 17 cP, about 6 cP to about 18 cP, about 6 cP to about 19
cP, about 6 cP to
about 20 cP, about 7 cP to about 10 cP, about 7 cP to about 11 cP, about 7 cP
to about 12 cP,
about 7 cP to about 13 cP, about 7 cP to about 14 cP, about 7 cP to about 15
cP, about 7 cP to
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about 16 cP, about 7 cP to about 17 cP, about 7 cP to about 18 cP, about 7 cP
to about 19 cP,
about 7 cP to about 20 cP, about 8 cP to about 10 cP, about 8 cP to about 11
cP, about 8 cP to
about 12 cP, about 8 cP to about 13 cP, about 8 cP to about 14 cP, about 8 cP
to about 15 cP,
about 8 cP to about 16 cP, about 8 cP to about 17 cP, about 8 cP to about 18
cP, about 8 cP to
about 19 cP, or about 8 cP to about 20 cP, at a concentration of about 150
mg/ml to about 300
mg/ml, about 150 mg/ml to about 200 mg/ml, or about 150, 155, 160, 165, 170,
175, 180,
185, 190, 195, 200, 205, 210,215, 220, or 225 mg/ml. In some embodiments, the
anti-T1LA
antibody is characterized by a viscosity about or less than about 20, 19, 18,
17, 16, 15, 14, 13,
12, 11, 10, 9, 8, 7, 6, or 5 mPa-s at a concentration greater than or about
150 mg/mL. In some
embodiments, the anti-T1LA antibody is characterized by a viscosity about or
less than about
20, 19, 18, 17, 16, 15,14, 13,12, 11, 10, 9, 8, 7, 6, or 5 mPa-s at a
concentration greater than
or about 160 mg/mL. In some embodiments, the anti-T1LA antibody is
characterized by a
viscosity about or less than about 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10,
9, 8, 7, 6, or 5
mPa-s at a concentration greater than or about 170 mg/mL. In some embodiments,
the anti-
T1LA antibody is characterized by a viscosity about or less than about 20, 19,
18, 17, 16, 15,
14, 13, 12, 11, 10,9, 8, 7,6, or 5 mPa-s at a concentration greater than or
about 180 mg/mL.
In some embodiments, the anti-T1LA antibody is characterized by a viscosity
about or less
than about 20, 19, 18,17, 16,15, 14,13, 12,11, 10, 9, 8, 7, 6, or 5 mPa-s at a
concentration
greater than or about 190 mg/mL. In some embodiments, the anti-T1LA antibody
is
characterized by a viscosity about or less than about 20, 19, 18, 17, 16, 15,
14, 13, 12, 11, 10,
9, 8, 7, 6, or 5 mPa-s at a concentration greater than or about 200 mg/mL. In
some
embodiments, the anti-T1LA antibody is characterized by a viscosity about or
less than about
20, 19, 18, 17, 16, 15,14, 13,12, 11, 10, 9, 8, 7, 6, or 5 mPa-s at a
concentration greater than
or about 210 mg/mL. In some embodiments, the anti-Ti LA antibody is
characterized by a
viscosity about or less than about 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10,
9, 8, 7, 6, or 5
mPa-s at a concentration greater than or about 220 mg/mL. In some embodiments,
the anti-
Ti LA antibody is characterized by a viscosity about or less than about 20,
19, 18, 17, 16, 15,
14, 13, 12, 11, 10, 9, 8, 7, 6, or 5 mPa-s at a concentration greater than or
about 230 mg/mL.
In some embodiments, the anti-T1LA antibody is characterized by a viscosity
about or less
than about 20, 19, 18,17, 16,15, 14,13, 12,11, 10, 9, 8, 7, 6, or 5 mPa-s at a
concentration
greater than or about 240 mg/mL. In some embodiments, the anti-T1LA antibody
is
characterized by a viscosity about or less than about 20, 19, 18, 17, 16, 15,
14, 13, 12, 11, 10,
9, 8, 7,6, or 5 mPa-s at a concentration greater than or about 250 mg/mL. In
some
embodiments, the anti-T1LA antibody is characterized by a viscosity about or
less than about
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20, 19, 18 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, or 5 mPa-s at a
concentration of about 150
mg/ml to about 250 mg/ml. In some embodiments, less than about 20 mPa-s
includes from
about 2 to about 20 mPa-s, from about 2 to about 19 mPa-s, from about 2 to
about 18 mPa-s,
from about 2 to about 17 mPa-s, from about 2 to about 16 mPa-s, from about 2
to about 15
mPa-s, from about 2 to about 14 mPa-s, from about 2 to about 13 mPa-s, from
about 2 to
about 12 mPa-s, from about 2 to about 11 mPa-s, from about 2 to about 10 mPa-
s, from about
2 to about 9 mPa-s, from about 2 to about 8 mPa-s, from about 2 to about 7 mPa-
s, from
about 2 to about 6 mPa-s, from about 2 to about 5 mPa-s, from about 3 to about
20 mPa-s,
from about 3 to about 19 mPa-s, from about 3 to about 18 mPa-s, from about 3
to about 17
mPa-s, from about 3 to about 16 mPa-s, from about 3 to about 15 mPa-s, from
about 3 to
about 14 mPa-s, from about 3 to about 13 mPa-s, from about 3 to about 12 mPa-
s, from about
3 to about 11 mPa-s, from about 3 to about 10 mPa-s, from about 3 to about 9
mPa-s, from
about 3 to about 8 mPa-s, from about 3 to about 7 mPa-s, from about 3 to about
6 mPa-s,
from about 3 to about 5 mPa-s, from about 4 to about 20 mPa-s, from about 4 to
about 19
mPa-s, from about 4 to about 18 mPa-s, from about 4 to about 17 mPa-s, from
about 4 to
about 16 mPa-s, from about 4 to about 15 mPa-s, from about 4 to about 14 mPa-
s, from about
4 to about 13 mPa-s, from about 4 to about 12 mPa-s, from about 4 to about 11
mPa-s, from
about 4 to about 10 mPa-s, from about 4 to about 9 mPa-s, from about 4 to
about 8 mPa-s,
from about 4 to about 7 mPa-s, from about 4 to about 6 mPa-s, from about 4 to
about 5 mPa-
s, from about 5 to about 20 mPa-s, from about 5 to about 19 mPa-s, from about
5 to about 18
mPa-s, from about 5 to about 17 mPa-s, from about 5 to about 16 mPa-s, from
about 5 to
about 15 mPa-s, from about 5 to about 14 mPa-s, from about 5 to about 13 mPa-
s, from about
to about 12 mPa-s, from about 5 to about 11 mPa-s, from about 5 to about 10
mPa-s, from
about 5 to about 9 mPa-s, from about 5 to about 8 mPa-s, from about 5 to about
7 mPa-s,
from about 5 to about 6 mPa-s, from about 6 to about 20 mPa-s, from about 6 to
about 19
mPa-s, from about 6 to about 18 mPa-s, from about 6 to about 17 mPa-s, from
about 6 to
about 16 mPa-s, from about 6 to about 15 mPa-s, from about 6 to about 14 mPa-
s, from about
6 to about 13 mPa-s, from about 6 to about 12 mPa-s, from about 6 to about 11
mPa-s, from
about 6 to about 10 mPa-s, from about 6 to about 9 mPa-s, from about 6 to
about 8 mPa-s, or
from about 6 to about 7 mPa-s. In some embodiments, greater than about 100,
125, 150, 160,
170, 180, 190, or 200 mg/ml is up to about 250 mg/ml.
1002811 Additionally, for example, in some embodiments, the anti-TL1A antibody
is
characterized by a turbidity less than 12 Nephelometric Turbidity Units (NTU)
when at a
concentration greater than about 100 mg/mL e.g., about 150 mg/mL to about 300
mg/mL,
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about 150 mg/mL to about 200 mg/mL, about 150 mg/mL to about 225 mg/mL, or
about 150
mg/mL to about 250 mg/mL. In some cases, the antibody comprises a HCDRI
comprising
SEQ ID NO: 1, a HCDR2 comprising SEQ ID NO: 2, a HCDR3 comprising SEQ ID NO:
6,
a LCDR1 comprising SEQ ID NO: 10, a LCDR2 comprising SEQ ID NO: 11, and a
LCDR3
comprising SEQ ID NO: 12, and/or having a heavy chain variable region
comprising SEQ ID
NO: 104 and a light chain variable region comprising SEQ ID NO: 201. In some
cases, the
anti-TL1A antibody comprises a human IGHV1-46*02 framework or a modified human
IGHV1-46*02 framework, and a light chain variable framework region comprising
a human
IGKV3-20 framework or a modified human IGKV3-20 framework; wherein the heavy
chain
variable framework region and the light chain variable framework region
collectively
comprise less than 9 amino acid modifications from the human IGHV1-46*02
framework and
the human IGKV3 -20 framework. In some embodiments, the anti-TL1A antibody is
characterized by a turbidity less than 12 Nephelometric Turbidity Units (NTU)
when at a
concentration greater than at least about 150 mg/mL. In some embodiments, the
anti-TLIA
antibody is characterized by a turbidity less than 12 Nephelometric Turbidity
Units (NTU)
when at a concentration greater than at least about 160 mg/mL. In some
embodiments, the
anti-TLIA antibody is characterized by a turbidity less than 12 Nephelometric
Turbidity
Units (NTU) when at a concentration greater than at least about 170 mg/mL. In
some
embodiments, the anti-TL1A antibody is characterized by a turbidity less than
12
Nephelometric Turbidity Units (NTU) when at a concentration greater than at
least about 180
mg/mL. In some embodiments, the anti-TL1A antibody is characterized by a
turbidity less
than 12 Nephelometric Turbidity Units (NTU) when at a concentration greater
than at least
about 190 mg/mL. In some embodiments, the anti-TLIA antibody is characterized
by a
turbidity less than 12 Nephelometric Turbidity Units (NTU) when at a
concentration of about
150 mg/mL to about 250 mg/mL. Less than 12 NTU may include about 1,2, 3,4, or
5 NTU
to about 12 NTU.
1002821 Additionally, anti-TLIA antibodies described herein also demonstrate
advantageous aggregation properties. In some embodiments, the anti-TL1A
antibody
composition is characterized by percent high molecular weight species (e.g., a
species having
a molecular weight greater than the molecular weight of the monomer) is less
than 10% of the
composition when the antibody is present in the composition at a concentration
greater than
about 100 mg/mL, e.g., about 150 mg/mL to about 300 mg/mL, about 150 mg/mL to
about
200 mg/mL, about 150 mg/mL to about 225 mg/mL, or about 150 mg/mL to about 250
mg/mL. In some cases, the antibody comprises a HCDRI comprising SEQ ID NO: 1,
a
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HCDR2 comprising SEQ ID NO: 2, a HCDR3 comprising SEQ ID NO: 6, a LCDR1
comprising SEQ ID NO: 10, a LCDR2 comprising SEQ ID NO: 11, and a LCDR3
comprising SEQ ID NO: 12, and/or having a heavy chain variable region
comprising SEQ ID
NO: 104 and a light chain variable region comprising SEQ ID NO: 201. In some
cases, the
anti-TL1A antibody comprises a human IGHV1-46*02 framework or a modified human
IGHV1-46*02 framework, and a light chain variable framework region comprising
a human
IGKV3-20 framework or a modified human IGKV3-20 framework; wherein the heavy
chain
variable framework region and the light chain variable framework region
collectively
comprise less than 9 amino acid modifications from the human IGHV I -46*02
framework and
the human IGKV3 -20 framework. In some embodiments, the anti-TL1A antibody
composition is characterized by percent high molecular weight species less
than 10%, 9%,
8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% when at a concentration greater than at
least about 150
mg/mL. In some embodiments, the anti-TL1A antibody composition is
characterized by
percent high molecular weight species less than 10%, 9%, 8%, 7%, 6%, 5%, 4%,
3%, 2%, or
1% when at a concentration greater than at least about 160 mg/mL. In some
embodiments,
the anti-TL1A antibody composition is characterized by percent high molecular
weight
species less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% when at a
concentration
greater than at least about 170 mg/mL. In some embodiments, the anti-TL1A
antibody
composition is characterized by percent high molecular weight species less
than 10%, 9%,
8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% when at a concentration greater than at
least about 180
mg/mL. In some embodiments, the anti-TL1A antibody composition is
characterized by
percent high molecular weight species less than 10%, 9%, 8%, 7%, 6%, 5%, 4%,
3%, 2%, or
1% when at a concentration greater than at least about 190 mg/mL. In some
embodiments,
the anti-TL1A antibody composition is characterized by percent high molecular
weight
species less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% when at a
concentration
greater than at least about 200 mg/mL. In some embodiments, the anti-TL1A
antibody
composition is characterized by percent high molecular weight species less
than 10%, 9%,
8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% when at a concentration greater than at
least about 210
mg/mL. In some embodiments, the anti-TL1A antibody composition is
characterized by
percent high molecular weight species less than 10%, 9%, 8%, 7%, 6%, 5%, 4%,
3%, 2%, or
1% when at a concentration greater than at least about 220 mg/mL. In some
embodiments,
the anti-TL1A antibody composition is characterized by percent high molecular
weight
species less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% when at a
concentration
greater than at least about 230 mg/mL. In some embodiments, the anti-TL1A
antibody
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composition is characterized by percent high molecular weight species less
than 10%, 9%,
8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% when at a concentration greater than at
least about 240
mg/mL. In some embodiments, the anti-TL1A antibody composition is
characterized by
percent high molecular weight species less than 10%, 9%, 8%, 7%, 6%, 5%, 4%,
3%, 2%, or
1% when at a concentration greater than at least about 250 mg/mL. In some
embodiments,
the anti-TL1A antibody composition is characterized by percent high molecular
weight
species less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% when at a
concentration of
about 150 mg/mL to about 250 mg/mL.
1002831 In some embodiments, provided are pharmaceutical compositions
comprising
about 150 mg to about 225 mg of anti-TL1A in a total volume of less than or
equal to about 1
mL. The composition may be formulated for subcutaneous administration. In some
cases, the
composition comprises about 150, 155, 160, 165, 170, 175, 180, 185, 190, 195,
200, 205,
210, 215, 220,225,230,235,240, 245,250,255,260,265,270,275,280,285,290,295,
300, 350, 400, 450, 500, 550,600, 650, 700, 750, 800, 850, 900,950,1000,
1100,1200,
1300, 1400,1500, 1600,1700, 1800, 1900, or 2000 mg of anti-TL1A. The total
volume may
be less than about 1.0,0.9, or 0.8 mL if less than 300 mg of anti-TL1A. The
total volume
may be at least about 0.5 mL if less than 300 mg of anti-TL1A. The total
volume may be
about 0.5 mL to about 3 mL, about 0.5 mL to about 2.9 mL, about 0.5 mL to
about 2.8 mL,
about 0.5 mL to about 2.7 mL, about 0.5 mL to about 2.6 mL, about 0.5 mL to
about 2.5 mL,
about 0.5 mL to about 2.4 mL, about 0.5 mL to about 2.3 mL, about 0.5 mL to
about 2.2 mL,
about 0.5 mL to about 2.1 mL, about 0.5 mL to about 2 mL, 0.5 mL to about 1.9
mL, 0.5 mL
to about 1.8 mL, 0.5 mL to about 1.7 mL, 0.5 mL to about 1.6 mL, about 0.5 mL
to about 1.0
mL, about 0.5 mL to about 0.9 mL, about 0.5 mL to about 0.8 mL, about 0.6 mL
to about 3
mL, about 0.6 mL to about 2.9 mL, about 0.6 mL to about 2.8 mL, about 0.6 mL
to about 2.7
mL, about 0.6 mL to about 2.6 mL, about 0.6 mL to about 2.5 mL, about 0.6 mL
to about 2.4
mL, about 0.6 mL to about 2.3 mL, about 0.6 mL to about 2.2 mL, about 0.6 mL
to about 2.1
mL, about 0.6 mL to about 2.0 mL, about 0.6 mL to about 1.9 mL, about 0.6 mL
to about 1.8
mL, about 0.6 mL to about 1.7 mL, about 0.6 mL to about 1.6 mL, about 0.6 mL
to about 1.5
mL, about 0.6 mL to about 1.4 mL, about 0.6 mL to about 1.3 mL, about 0.6 mL
to about 1.2
mL, about 0.6 mL to about 1.1 mL, about 0.6 mL to about 1.0 mL, about 0.6 mL
to about 0.9
mL, about 0.6 mL to about 0.8 mL, about 0.7 mL to about 3 mL, about 0.7 mL to
about 2.9
mL, about 0.7 mL to about 2.8 mL, about 0.7 mL to about 2.7 mL, about 0.7 mL
to about 2.6
mL, about 0.7 mL to about 2.5 mL, about 0.7 mL to about 2.4 mL, about 0.7 mL
to about 2.3
mL, about 0.7 mL to about 2.2 mL, about 0.7 mL to about 2.1 mL, about 0.7 mL
to about 2.0
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mL, about 0.7 mL to about 1.9 mL, about 0.7 mL to about 1.8 mL, about 0.7 mL
to about 1.7
mL, about 0.7 mL to about 1.6 mL, about 0.7 mL to about 1.5 mL, about 0.7 mL
to about 1.4
mL, about 0.7 mL to about 1.3 mL, about 0.7 mL to about 1.2 mL, about 0.7 mL
to about 1.1
mL, about 0.7 mL to about 1.0 mL, about 0.7 mL to about 0.9 mL, about 0.7 mL
to about 0.8
mL, about 3 mL to about 10 mL, about 3 mL to about 9.5 mL, about 3 mL to about
9.0 mL,
about 3 mL to about 8.5 mL, about 3 mL to about 8.0 mL, about 3 mL to about
7.5 mL, about
3 mL to about 7.0 mL, about 3 mL to about 6.5 mL, about 3 mL to about 6 mL,
about 3 mL
to about 5.5 mL, about 3 mL to about 5.0 mL, about 3 mL to about 4.5 mL, about
3 mL to
about 4 mL, about 3 mL to about 3.5 mL, about 3.5 mL to about 10 mL, about 3.5
mL to
about 9.5 mL, about 3.5 mL to about 9.0 mL, about 3.5 mL to about 8.5 mL,
about 3.5 mL to
about 8.0 mL, about 3.5 mL to about 7.5 mL, about 3.5 mL to about 7.0 mL,
about 3.5 mL to
about 6.5 mL, about 3.5 mL to about 6 mL, about 3.5 mL to about 5.5 mL, about
3.5 mL to
about 5.0 mL, about 3.5 mL to about 4.5 mL, about 3.5 mL to about 4 mL, about
4.0 mL to
about 10 mL, about 4.0 mL to about 9.5 mL, about 4.0 mL to about 9.0 mL, about
4.0 mL to
about 8.5 mL, about 4.0 mL to about 8.0 mL, about 4.0 mL to about 7.5 mL,
about 4.0 mL to
about 7.0 mL, about 4.0 mL to about 6.5 mL, about 4.0 mL to about 6 mL, about
4.0 mL to
about 5.5 mL, about 4.0 mL to about 5.0 mL, about 4.0 mL to about 4.5 mL,
about 4.5 mL to
about 10 mL, about 4.5 mL to about 9.5 mL, about 4.5 mL to about 9.0 mL, about
4.5 mL to
about 8.5 mL, about 4.5 mL to about 8.0 mL, about 4.5 mL to about 7.5 mL,
about 4.5 mL to
about 7.0 mL, about 4.5 mL to about 6.5 mL, about 4.5 mL to about 6 mL, about
4.5 mL to
about 5.5 mL, about 4.5 mL to about 5.0 mL, about 5 mL to about 10 mL, about 5
mL to
about 9.5 mL, about 5 mL to about 9.0 mL, about 5 mL to about 8.5 mL, about 5
mL to about
8.0 mL, about 5 mL to about 7.5 mL, about 5 mL to about 7.0 mL, about 5 mL to
about 6.5
mL, about 5 mL to about 6 mL, about 5 mL to about 5.5 mL, about 5.5 mL to
about 10 mL,
about 5.5 mL to about 9.5 mL, about 5.5 mL to about 9.0 mL, about 5.5 mL to
about 8.5 mL,
about 5.5 mL to about 8.0 mL, about 5.5 mL to about 7.5 mL, about 5.5 mL to
about 7.0 mL,
about 5.5 mL to about 6.5 mL, about 5.5 mL to about 6 mL, about 6.0 mL to
about 10 mL,
about 6.0 mL to about 9.5 mL, about 6.0 mL to about 9.0 mL, about 6.0 mL to
about 8.5 mL,
about 6.0 mL to about 8.0 mL, about 6.0 mL to about 7.5 mL, about 6.0 mL to
about 7.0 mL,
about 6.0 mL to about 6.5 mL, about 6.5 mL to about 10 mL, about 6.5 mL to
about 9.5 mL,
about 6.5 mL to about 9.0 mL, about 6.5 mL to about 8.5 mL, about 6.5 mL to
about 8.0 mL,
about 6.5 mL to about 7.5 mL, about 6.5 mL to about 7.0 mL, about 7.0 mL to
about 10 mL,
about 7.0 mL to about 9.5 mL, about 7.0 mL to about 9.0 mL, about 7.0 mL to
about 8.5 mL,
about 7.0 mL to about 8.0 mL, about 7.0 mL to about 7.5 mL, about 7.5 mL to
about 10 mL,
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about 7.5 mL to about 9.5 mL, about 7.5 mL to about 9.0 mL, about 7.5 mL to
about 8.5 mL,
about 7.5 mL to about 8.0 mL, about 8.0 mL to about 10 mL, about 8.0 mL to
about 9.5 mL,
about 8.0 mL to about 9.0 mL, about 8.0 mL to about 8.5 mL, about 8.5 mL to
about 10 mL,
about 8.5 mL to about 9.5 mL, about 8.5 mL to about 9.0 mL, about 9 mL to
about 10 mL,
about 9 mL to about 9.5 mL, or about 9.5 mL to about 10 mL. In some
embodiments, the
concentration of anti-TL1A is about or greater than about 55, 60, 65, 70, 75,
80, 85, 90, 95,
100, 105, 110, 115, 120, 125,130, 135, 140, 145, 155, 160, 165, 170, 175, 180,
185, 190,
195, 200, 205, 210, 215, 220,225, 230, 235, 240, 245, or 250 mg,/mL.
1002841 In some embodiments, provided are pharmaceutical compositions
comprising
about 400 mg to about 1000 mg or 400 mg to 2000 mg of anti-TL1A in a total
volume of less
than or equal to about 15 mL. The composition may be formulated for
intravenous
administration. The composition may be diluted into about 100 to about 300, or
about 250
mL pharmaceutically acceptable solution (e.g., saline) for intravenous
administration. The
total volume may be at least about 1 mL, at least about 2 mL, at least about
2.5 mL, at least
about 3 mL, at least about 4 mL, or at least about 5 mL; and less than or
equal to about 15
mL, 14 mL, 13 mL, 11 mL, or 10 mL. For instance, the volume may be from about
1 mL to
about 15 mL, from about 1 mL to about 14 mL, from about 1 mL to about 13 mL,
from about
1 mL to about 12 mL, from about 1 mL to about 11 mL, from about 1 mL to about
10 mL,
from about 1 mL to about 9 mL, from about 1 mL to about 8 mL, from about 1 mL
to about 7
mL, from about 1 mL to about 6 mL, from about 1 mL to about 5 mL, from about 1
mL to
about 4 mL, from about 1 mL to about 3 mL, from about 1 mL to about 2 mL, from
about 2
mL to about 15 mL, from about 2 mL to about 14 mL, from about 2 mL to about 13
mL, from
about 2 mL to about 12 mL, from about 2 mL to about 11 mL, from about 2 mL to
about 10
mL, from about 2 mL to about 9 mL, from about 2 mL to about 8 mL, from about 2
mL to
about 7 mL, from about 2 mL to about 6 mL, from about 2 mL to about 5 mL, from
about 2
mL to about 4 mL, from about 2 mL to about 3 mL, from about 3 mL to about 15
mL, from
about 3 mL to about 14 mL, from about 3 mL to about 13 mL, from about 3 mL to
about 12
mL, from about 3 mL to about 11 mL, from about 3 mL to about 10 mL, from about
3 mL to
about 9 mL, from about 3 mL to about 8 mL, from about 3 mL to about 7 mL, from
about 3
mL to about 6 mL, from about 3 mL to about 5 mL, from about 3 mL to about 4
mL, from
about 4 mL to about 15 mL, from about 4 mL to about 14 mL, from about 4 mL to
about 13
mL, from about 4 mL to about 12 mL, from about 4 mL to about 11 mL, from about
4 mL to
about 10 mL, from about 4 mL to about 9 mL, from about 4 mL to about 8 mL,
from about 4
mL to about 7 mL, from about 4 mL to about 6 mL, from about 4 mL to about 5
mL, from
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about 5 mL to about 15 mL, from about 5 mL to about 14 mL, from about 5 mL to
about 13
mL, from about 5 mL to about 12 mL, from about 5 mL to about 11 mL, from about
5 mL to
about 10 mL, from about 5 mL to about 9 mL, from about 5 mL to about 8 mL,
from about 5
mL to about 7 mL, or from about 5 mL to about 6 mL.
1002851 Non-limiting example excipients
1002861 In certain embodiments, a pharmaceutical composition comprising an
anti-TL1A
antibody comprises a surfactant. A surfactant includes a nonionic surfactant,
ionic surfactant,
and amphoteric surfactant, and combinations thereof. In some embodiments, the
surfactant
comprises a nonionic surfactant. Non-limiting examples of non-ionic
surfactants include
polysorbate, polyglycerol alkyl ether, glucosyl dialkyl ether, crownether,
ester-linked
surfactant, polyoxyethylene alkyl ether, poloxamer 18, Brij, Spans (sorbitan
ester), Triton X-
100 (polyethylene glycol p- (1,1,3,3-tetramethylbutyl) -phenyl ether), poly
oxyethylene (35)
dodecyl ether, polyethylene glycol hexadecyl ether, polyoxyethylene (20) oleyl
ether,
polyoxyethylene (9) lauryl alcohol, poly ethoxylated (35) castor oil,
octylphenoxypoly(ethyleneoxy) ethanol, poly(oxyethylene-cooxypropylene) block
copolymer, poly(oxyethylene-cooxypropylene) block copolymer, poly(oxyethylene-
cooxypropylene) block copolymer, polydimethylsiloxane methylethoxylate, p-
Isononylphenoxy-poly(glycidol), 2,4,7,9-tetramethy1-5-decyne-4,7- diol
ethoxylate,
polyethylene glycol-polypropylene glycol-polyethyleneglycol triblock polymer,
and
nonylphenol ethoxylate, and combinations thereof. In some embodiments, the
surfactant
comprises an ionic surfactant. Ionic surfactants include anionic and cationic
surfactants. Non-
limiting examples of anionic surfactants include alkyl sulfate, alkyl ether
sulfate, docusate,
sulfonate fluorosurfactant, alkyl benzene sulfonate, alkyl aryl ether
phosphate, alkyl ether
phosphate, alkyl carboxylate, and sodium dioctyl-sulfosuccinate, and
combinations thereof.
Non-limiting examples of cationic surfactants include cetyltrimethylammonium
bromide
(CTAB), cetyltrimethylammonium chloride (CTAC), cetylpyridinium chloride
(CPC),
polyethoxylated tallow amine (POEA), benzalkonium chloride (BAC), benzethonium
chloride (BZT), 5-bromo-5-nitro-1,3-dioxane, dimethyl dioctadecyl ammonium
chloride, and
dioctadecyl dimethyl ammonium bromide (DODAB), and combinations thereof. In
some
embodiments, the surfactant comprises an amphoteric surfactant. An example
amphoteric
surfactant includes ethylenediamine tetrakis (ethoxylate-block-propoxylate)
tetrol.
1002871 In example embodiments, the surfactant comprises polysorbate.
Polysorbate
includes, without limitation, polysorbate-20, p oly sorb ate-60, and poly
sorbate-80, and
combinations thereof. The polysorbate may be polysorbate-20.
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1002881 In some embodiments of the composition provided herein, the
composition
comprises a surfactant, wherein the surfactant comprises or consists of
polysorbate-20. In
some embodiments of the composition provided herein, the surfactant comprises
or consists
of poly sorb ate-20.
1002891 In some embodiments, the surfactant is present in the composition at a
concentration of about 0.001-0.1% v/v of the composition. For instance, the
surfactant is
present at a concentration of about 0.005% to about 0.05%, about 0.01% to
about 0.05%,
about 0.005% to about 0.04%, about 0.01% to about 0.04%, about 0.005% to about
0.03%,
about 0.01% to about 0.03%, about 0.005% to about 0.02%, or about 0.01% to
about 0.02%
v/v of the composition. In example embodiments, the surfactant comprises about
0.01% to
about 0.05%, or about 0.01%, about 0.02%, about 0.03%, about 0.04%, or about
0.05% v/v of
the composition. As a further embodiment, the surfactant comprises about 0.01%
to about
0.05%, or about 0.01%, about 0.02%, about 0.03%, about 0.04%, or about 0.05%
polysorbate
in the composition. For instance, some embodiments of the compositions
comprise about
0.01%-0.02%, or about 0.01% or about 0.02% polysorbate. In one embodiment of
the
composition provided herein, the composition comprises polysorbate-20 at a
concentration of
about 0.01% to about 0.05%, or about 0.005%, about 0.006%, about 0.007%, about
0.008%,
about 0.009%, about 0.01%, about 0.011%, about 0.012%, about 0.013%, about
0.014%,
about 0.015%, about 0.016%, about 0.017%, about 0.018%, about 0.019%, about
0.02%,
about 0.021%, about 0.022%, about 0.023%, about 0.024%, about 0.025%, about
0.026%,
about 0.027%, about 0.028%, about 0.029%, or about 0.03% v/v of the
composition. In one
embodiment of the composition provided herein, the composition comprises
polysorbate -20
at a concentration of about 0.02% v/v of the composition. In one embodiment of
the
composition provided herein, the composition comprises polysorbate-60 at a
concentration of
about 0.01% to about 0.05%, or about 0.005%, about 0.006%, about 0.007%, about
0.008%,
about 0.009%, about 0.01%, about 0.011%, about 0.012%, about 0.013%, about
0.014%,
about 0.015%, about 0.016%, about 0.017%, about 0.018%, about 0.019%, about
0.02%,
about 0.021%, about 0.022%, about 0.023%, about 0.024%, about 0.025%, about
0.026%,
about 0.027%, about 0.028%, about 0.029%, or about 0.03% v/v of the
composition. In one
embodiment of the composition provided herein, the composition comprises
polysorbate-60
at a concentration of about 0.02% v/v of the composition. In one embodiment of
the
composition provided herein, the composition comprises polysorbate-80 at a
concentration of
about 0.01% to about 0.05%, or about 0.005%, about 0.006%, about 0.007%, about
0.008%,
about 0.009%, about 0.01%, about 0.011%, about 0.012%, about 0.013%, about
0.014%,
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about 0.015%, about 0.016%, about 0.017%, about 0.018%, about 0.019%, about
0.02%,
about 0.021%, about 0.022%, about 0.023%, about 0.024%, about 0.025%, about
0.026%,
about 0.027%, about 0.028%, about 0.029%, or about 0.03% v/v of the
composition. In one
embodiment of the composition provided herein, the composition comprises
polysorbate-80
at a concentration of about 0.02% v/v of the composition.
1002901 In certain embodiments, a pharmaceutical composition comprising an
anti-TL1A
antibody comprises a stabilizer. Stabilizers include sugars, polyols, amino
acids, polymers,
and cyclodextrin (e.g., HP-b-CD), and combinations thereof. In some
embodiments, the
stabilizer comprises a sugar. Non-limiting examples of sugars include sucrose,
glucose,
trehalose, maltose, and lactose, and combinations thereof. In some
embodiments, the
stabilizer comprises a polyol. Non-limiting examples of polyols include
mannitol, sorbitol,
raffinose, and glycerol, and combinations thereof. In exemplary embodiments,
the stabilizer
comprises a sugar, such as sucrose. In some embodiments, the sugar comprises
or consists of
sucrose. In some embodiments, the stabilizer comprises an amino acid. In some
embodiments, the amino acid comprises or consists of glycine. In some
embodiments, the
amino acid comprises or consists of glycine. In some embodiments, the
stabilizer comprises
both a sugar and an amino acid. In some embodiments, the stabilizer comprises
both sucrose
and glycine.
1002911 In some embodiments, the stabilizer is present in the composition at a
concentration of about 50 mM to about 300 mM. For instance, the stabilizer is
present at a
concentration of about 50 mM to about 300 mM, about 50 mM to about 290 mM,
about 50
mM to about 280 mM, about 50 mM to about 270 mM, about 50 mM to about 260 mM,
about 50 mM to about 250 mM, about 50 mM to about 240 mM, about 50 mM to about
220
mM, about 50 mM to about 200 mM, about 75 mM to about 300 mM, about 75 mM to
about
290 mM, about 75 mM to about 280 mM, about 75 mM to about 270 mM, about 75 mM
to
about 260 mM, about 75 mM to about 250 mM, about 75 mM to about 240 mM, about
75
mM to about 220 mM, about 75 mM to about 200 mM, about 100 mM to about 300 mM,
about 100 mM to about 290 mM, about 100 mM to about 280 mM, about 100 mM to
about
270 mM, about 100 mM to about 260 mM, about 100 mM to about 250 mM, about 100
mM
to about 240 mM, about 100 mM to about 220 mM, about 100 mM to about 200 mM,
about
125 mM to about 300 mM, about 125 mM to about 290 mM, about 125 mM to about
280
mM, about 125 mM to about 270 mM, about 125 mM to about 260 mM, about 125 mM
to
about 250 mM, about 125 mM to about 240 mM, about 125 mM to about 220 mM,
about 125
mM to about 200 mM, about 150 mM to about 300 mM, about 150 mM to about 290
mM,
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about 150 mM to about 280 mM, about 150 mM to about 270 mM, about 150 mM to
about
260 mM, about 150 mM to about 250 mM, about 150 mM to about 240 mM, about 150
mM
to about 220 mM, about 150 mM to about 200 mM, about 175 mM to about 300 mM,
about
175 mM to about 290 mM, about 175 mM to about 280 mM, about 175 mM to about
270
mM, about 175 mM to about 260 mM, about 175 mM to about 250 mM, about 175 mM
to
about 240 mM, about 175 mM to about 220 mM, about 175 mM to about 200 mM,
about 200
mM to about 300 mM, about 200 mM to about 290 mM, about 200 mM to about 280
mM,
about 200 mM to about 270 mM, about 200 mM to about 260 mM, about 200 mM to
about
250 mM, about 200 mM to about 240 mM, or about 200 mM to about 220 mM. In
example
embodiments, the stabilizer is present at concentrations of about 150 mM to
about 270 mM,
or about 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130,
135, 140, 145, 150,
160, 170, 180, 190,200,210,220,230,240,250, 260, or 270 mM stabilizer. As a
further
embodiment, the composition comprises about 150 mM to about 270 mM, or about
150, 160,
170, 180, 190,200,210,220,230, 240, 250, 260, or 270 mM sucrose, for instance,
about
220-240 mM, or about 220, about 230, or about 240 mM sucrose. In yet another
embodiment, the composition comprises about 50 mM to about 150 mM, or about
50, 55, 60,
65, 70, 75, 80, 85, 90,95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145,
150 mM glycine,
for instance, 75-100 mM or about 80, about 85, or about 90 mM glycine. In yet
another
embodiment, the composition comprises about 150 mM to about 270 mM, or about
150, 160,
170, 180, 190,200,210,220,230, 240, 250, 260, or 270 mM sucrose and comprises
50 mM
to about 150 mM, or about 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105,
110, 115, 120,
125, 130, 135, 140, 145, 150 mM glycine.
1002921 In certain embodiments, a pharmaceutical composition comprising an
anti-TL1A
antibody comprises a salt. Non-limiting examples of salt include sodium
chloride, glycine,
lysine-hydrochloride, arginine-hydrochloride, arginine glutamate, potassium
chloride,
magnesium chloride, and calcium chloride, and combinations thereof. In some
embodiments,
the salt comprises sodium chloride. In some embodiments, the salt comprises
lysine-HC1.
1002931 In some embodiments, the salt is present in the composition at a
concentration of
about 10 mM to about 150 mM. For instance, the salt is present at a
concentration of about 10
mM to about 150 mM, about 10 mM to about 140 mM, about 10 mM to about 130 mM,
about 10 mM to about 120 mM, about 10 mM to about 110 mM, about 10 mM to about
100
mM, about 10 mM to about 90 mM, about 10 mM to about 80 mM, about 10 mM to
about 70
mM, about 10 mM to about 60 mM, about 10 mM to about 50 mM, about 10 mM to
about 40
mM, about 10 mM to about 30 mM, about 20 mM to about 150 mM, about 20 mM to
about
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140 mM, about 20 mM to about 130 mM, about 20 mM to about 120 mM, about 20 mM
to
about 110 mM, about 20 mM to about 100 mM, about 20 mM to about 90 mM, about
20 mM
to about 80 mM, about 20 mM to about 70 mM, about 20 mM to about 60 mM, about
20 mM
to about 50 mM, about 20 mM to about 40 mM, about 20 mM to about 30 mM, about
30 mM
to about 150 mM, about 30 mM to about 140 mM, about 30 mM to about 130 mM,
about 30
mM to about 120 mM, about 30 mM to about 110 mM, about 30 mM to about 100 mM,
about 30 mM to about 90 mM, about 30 mM to about 80 mM, about 30 mM to about
70 mM,
about 30 mM to about 60 mM, about 30 mM to about 50 mM, about 30 mM to about
40 mM,
about 40 mM to about 150 mM, about 40 mM to about 140 mM, about 40 mM to about
130
mM, about 40 mM to about 120 mM, about 40 mM to about 110 mM, about 40 mM to
about
100 mM, about 40 mM to about 90 mM, about 40 mM to about 80 mM, about 40 mM to
about 70 mM, about 40 mM to about 60 mM, or about 40 mM to about 50 mM. In
example
embodiments, the salt is present at concentrations of about 25 mM to about 130
mM. As a
further embodiment, the composition comprises about 40 mM to about 130 mMNaCl.
For
instance, the composition comprises about 40 mMNaCl. In some embodiments, the
composition comprises about 10 mM, about 15 mM, about 20 mM, about 25 mM,
about 30
mM, about 35 mM, about 40 mM, about 45 mM, about 50 mM, about 55 mM, about 60
mM,
about 65 mM, about 70 mM, about 75 mM, about 80 mM, about 85 mM, about 90 mM,
about
95 mM, about 100 mM, about 105 mM, about 110 mM, about 115 mM, about 120 mM,
about
125 mM, about 130 mM, about 135 mM, about 140 mM, about 145 mM, or about 150
mM
NaCl. As a further embodiment, the composition comprises about 25 mM to about
50 mM
Ly s-HC1. For instance, the composition comprises about 25 mMLys-HC1.
1002941 In certain embodiments, a pharmaceutical composition comprising an
anti-TL1A
antibody comprises a buffering agent. Non-limiting examples of buffering
agents include an
acetate, phosphate, citrate, glutamate, succinate, g,luconate, histidine,
glycylglycine, citric
acid, Tris (tris (hydroxymethyl) aminomethane), and diethanolamine, and
combinations
thereof. In an example embodiment, the buffering agent comprises acetate. In
some
embodiments, the buffering agent comprises sodium acetate. In some
embodiments, the
buffering agent comprises acetic acid. In some embodiments, the buffering
agent comprising
acetate comprises acetic acid and sodium acetate. In some embodiments, the
buffering agent
comprises potassium acetate. In some embodiments, the buffering agent
comprises aluminum
acetate. In some embodiments, the buffering agent comprises ammonium acetate.
In some
embodiments, the buffering agent comprises phosphate. In one embodiment, the
buffering
agent comprising phosphate comprises phosphoric acid and sodium phosphate. In
some
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embodiments, the buffering agent comprises phosphoric acid and potassium
phosphate. In
some embodiments, the buffering agent comprises sodium phosphate dibasic and
sodium
phosphate monobasic. In some embodiments, the buffering agent comprises
phosphoric acid,
sodium phosphate dibasic, sodium phosphate monobasic, and/or sodium phosphate.
In some
embodiments, the buffering agent comprises potassium phosphate dibasic and
potassium
phosphate monobasic. In some embodiments, the buffering agent comprises
phosphoric acid,
potassium phosphate dibasic, potassium phosphate monobasic, and/or potassium
phosphate.
In some embodiments, the buffering agent is present in the composition at a
concentration of
about 5 mM to about 50 mM. For instance, the buffering agent is present at a
concentration of
about 5 mM to about 50 mM, about 5 mM to about 40 mM, about 5 mM to about 30
mM,
about 5 mM to about 20 mM, about 5 mM to about 10 mM, about 10 mM to about 50
mM,
about 10 mM to about 40 mM, about 10 mM to about 30 mM, or about 10 mM to
about 20
mM. As a non-limiting example, the buffering agent is present at a
concentration of about 10
mM to about 20 mM, or about 20 mM. As a further example embodiment, the
composition
comprises about 10 mM to about 20 mM, or about 10 mM or about 20 mM of
acetate. In a
further embodiment, the composition comprises about 10 mM to about 20 mM, or
about 10
mM or about 20 mM of phosphate.
1002951 In certain embodiments, a pharmaceutical composition comprising an
anti-TL1A
antibody has a pH of 4.0 to 8Ø For instance, the pH is about 4.5 to about
8.0, about 4.5 to
about 7.8, about 4.5 to about 7.6, about 4.5 to about 7.4, about 4.5 to about
7.2, about 4.5 to
about 7.0, about 4.5 to about 6.8, about 4.5 to about 6.6, about 4.5 to about
6.4, about 4.5 to
about 6.2, about 4.5 to about 6.0, about 4.5 to about 5.8, about 4.5 to about
5.6, about 4.5 to
about 5.4, about 4.5 to about 5.2, or about 4.5 to about 5Ø In some
embodiments, the pH is
about 4.5 to about 6.0, about 4.5 to about 5.9, about 4.5 to about 5.8, about
4.5 to about 5.7,
or about 4.5 to about 5.6. In example embodiments, the pH is about 4.5 to
about 5.5, or about
4.5 to about 5.4, about 4.5 to about 5.3, about 4.5 to about 5.2, about 4.5 to
about 5.1, about
4.5 to about 5.0, 4.6 to about 5.5, about 4.6 to about 5.4, about 4.6 to about
5.3, about 4.6 to
about 5.2, about 4.6 to about 5.1, about 4.6 to about 5.0, 4.7 to about 5.5,
about 4.7 to about
5.4, about 4.7 to about 5.3, about 4.7 to about 5.2, about 4.7 to about 5.1,
about 4.7 to about
5.0, 4.8 to about 5.5, about 4.8 to about 5.4, about 4.8 to about 5.3, about
4.8 to about 5.2,
about 4.8 to about 5.1, about 4.8 to about 5.0, 4.9 to about 5.5, about 4.9 to
about 5.4, about
4.9 to about 5.3, about 4.9 to about 5.2, about 4.9 to about 5.1, about 4.9 to
about 5.0, about
5.0 to about 5.5, about 5.0 to about 5.4, about 5.0 to about 5.3, about 5.0 to
about 5.2, about
5.0 to about 5.1, about 5.1 to about 5.5, about 5.1 to about 5.4, about 5.1 to
about 5.3, about
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5.1 to about 5.2, about 5.2 to about 5.5, about 5.2 to about 5.4, about 5.2 to
about 5.3, about
5.3 to about 5.5, about 5.3 to about 5.4, or about 5.4 to about 5.5. The pH
may be about 4.5 to
about 5.5, or about 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, or 5.5.
As an example, the pH
is about 5.3. In a non-limiting example, the composition comprises an acetate
buffer, with a
pH of about 4.5 to about 5.5, or about 5.3. In certrain embodiments, the pH is
about 6.0 to
about 7.0, about 6.0 to about 6.9, about 6.0 to about 6.8, about 6.0 to about
6.7, about 6.0 to
about 6.6, about 6.0 to about 6.5, about 6.0 to about 6.4, about 6.0 to about
6.3, about 6.0 to
about 6.2, about 6.0 to about 6.1, about 6.1 to about 7.0, about 6.1 to about
6.9, about 6.1 to
about 6.8, about 6.1 to about 6.7, about 6.1 to about 6.6, about 6.1 to about
6.5, about 6.1 to
about 6.4, about 6.1 to about 6.3, about 6.1 to about 6.2, about 6.2 to about
7.0, about 6.2 to
about 6.9, about 6.2 to about 6.8, about 6.2 to about 6.7, about 6.2 to about
6.6, about 6.2 to
about 6.5, about 6.2 to about 6.4, about 6.2 to about 6.3, about 6.3 to about
7.0, about 6.3 to
about 6.9, about 6.3 to about 6.8, about 6.3 to about 6.7, about 6.3 to about
6.6, about 6.3 to
about 6.5, about 6.3 to about 6.4, about 6.4 to about 7.0, about 6.4 to about
6.9, about 6.4 to
about 6.8, about 6.4 to about 6.7, about 6.4 to about 6.6, about 6.4 to about
6.5, about 6.5 to
about 7.0, about 6.5 to about 6.9, about 6.5 to about 6.8, about 6.5 to about
6.7, or about 6.5
to about 6.6. The pH can be about 6.0 to about 7.0, or about 6.1, 6.2, 6.3,
6.4, 6.5, 6.6, 6.7,
6.8, 6.9, or 7Ø As an example, the pH is about 6.5. In a non-limiting
example, the
composition comprises an phosphate buffer, with a pH of about 6.0 to about
7.0, or about 6.5.
[00296] In some embodiments, a pharmaceutical composition comprising an anti-
TL1A
antibody comprises one or more of the following: surfactant, stabilizer, salt,
and buffering
agent. In some embodiments, the pharmaceutical composition comprises a
surfactant and a
stabilizer. In some embodiments, the pharmaceutical composition comprises a
surfactant and
a salt. In some embodiments, the pharmaceutical composition comprises a
surfactant and a
buffering agent. In some embodiments, the pharmaceutical composition comprises
a
stabilizer and a salt. In some embodiments, the pharmaceutical composition
comprises a
stabilizer and a buffering agent. In some embodiments, the pharmaceutical
composition
comprises a salt and buffering agent. In some embodiments, the pharmaceutical
composition
comprises a surfactant, stabilizer, and salt. In some embodiments, the
pharmaceutical
composition comprises surfactant, salt, and buffering agent. In some
embodiments, the
pharmaceutical composition comprises a surfactant, stabilizer and buffering
agent. In some
embodiments, the pharmaceutical composition comprises a stabilizer, salt, and
buffering
agent. In some embodiments, the pharmaceutical composition comprises a
surfactant,
stabilizer, salt, and buffering agent.
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1002971 Non-limiting example pharmaceutical compositions comprise a nonionic
surfactant, sugar, salt and buffering agent. For instance, the compositions
comprise
polysorbate (e.g., polysorbate-20), sucrose, lysine-HC1 or sodium chloride,
and an acetate
buffer. The pH of the composition may be about 4.5 to about 5.5, or about 5.0
to about 5.5. In
an example embodiment, the composition comprises about 10-20 mM acetate at pH
4.5-5.5,
150-270 mM sucrose, 25-50 mMLys-HC1, and 0.01%-0.05%v/v polysorbate-20. For
instance, the composition comprises about 20 mM acetate at pH 5.3, about 240
mM sucrose,
about 25 mMlysine-HC1, and about 0.02% poly sorbate-20. As another example
embodiment,
the composition comprises about 10-20 mM acetate at pH 4.5-5.5, 150-270 mM
sucrose, 50-
130 mM NaCl, and 0.01%-0.05%v/v polysorbate-20. For instance, the composition
comprises about 20 mM acetate at pH 5.3, 220 mM sucrose, 40 mMNaC1, and 0.02%
poly sorb ate-20.
10029811 In some embodiments, the compositions comprise polysorbate (e.g.,
polysorbate-
20), sucrose, sodium chloride, and an acetate buffer. The pH of the
composition may be about
4.5 to about 5.5, or about 5.0 to about 5.5. In an example embodiment, the
composition
comprises about 10-20 mM acetate at pH 4.5-5.5, 1 50-270 mM sucrose, and 0.01%-
0.05%
v/v poly sorb ate-20. For instance, the composition comprises about 20 mM
acetate at pH 5.3,
about 220 mM sucrose, and about 0.02% polysorbate-20. As another example
embodiment,
the composition comprises about 10-20 mM acetate at pH 4.5-5.5, 150-270 mM
sucrose, 50-
130 mM NaCl, and 0.01%-0.05%v/v polysorbate-20. For instance, the composition
comprises about 20 mM acetate at pH 5.3, 220 mM sucrose, 40 mMNaC1, and 0.02%
polysorbate-20.
1002991 In some embodiments, the compositions comprise polysorbate (e.g.,
polysorbate-
20), sucrose, glycine, sodium chloride, and a phosphate buffer. In certain
embodiments, the
compositions comprise polysorbate (e.g., polysorbate-20), sucrose, glycine,
and a phosphate
buffer. In some embodiments, the compositions comprise polysorbate-20,
sucrose, glycine,
and a phosphate buffer. The pH of the composition may be about 6.0 to about
7.0, or about
6.5 to about 7Ø In an example embodiment, the composition comprises about 10-
20 mM
phosphate at pH 6.0-7.0, 75-100 mM glycine, 100-270 mM sucrose, and 0.01%-
0.05% v/v
polysorbate-20. For instance, the composition comprises about 20 mM phosphate
at pH 6.5,
about 85mM glycine, about 146 mM sucrose, and about 0.02% polysorbate-20. As
another
example embodiment, the composition comprises about 10-20 mM phosphate at pH
6.0-7.0,
75-100mM glycine, 2% to 8% (w/v) sucrose, and 0.01%-0.05%v/v polysorbate-20.
For
instance, the composition comprises about 20 mM phosphate at pH 6.5, 5% (w/v)
sucrose, 85
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mM glycine, and 0.02% polysorbate-20.
1003001 In one embodiment, provided herein is a composition comprising an anti-
TL1A
antibody provided herein at a concentration of about 200 mg/mL, 20 mM sodium
acetate, 220
mM sucrose, 40 mMNaC1, and 0.02% polysorbate-20, at pH 5.3. In another
embodiment,
provided herein is a composition comprising an anti-TL1A antibody provided
herein at a
concentration of about 100 mg/mL, 20 mM sodium acetate, 220 mM sucrose, 40 mM
NaC1,
and 0.02% polysorbate-20, at pH 5.3. In another embodiment, provided herein is
a
composition comprising an anti-TL1A antibody provided herein at a
concentration of about
60 mg/mL, 20 mM sodium phosphate, 5% sucrose, 85 mM glycine, and 0.02%
polysorbate-
20, at pH 5.3. In one embodiment, provided herein is a composition comprising
an anti-
TL1A antibody provided herein at a concentration described herein, 20 mM
sodium acetate,
220 mM sucrose, 40 mMNaC1, and 0.02% poly sorbate-20, at pH 5.3. In another
embodiment, provided herein is a composition comprising an anti-TL1A antibody
provided
herein at a concentration described herein, 20 mM sodium acetate, 220 mM
sucrose, 40 mM
NaC1, and 0.02% polysorbate-20, at pH 5.3. In another embodiment, provided
herein is a
composition comprising an anti-TL1A antibody provided herein at a
concentration described
herein, 20 mM sodium phosphate, 5% sucrose, 85 mM glycine, and 0.02%
polysorbate-20, at
pH 5.3. In one embodiment, provided herein is a composition comprising an anti-
TL1A
antibody provided herein at a concentration of about 150 mg/ml to 250 mg/ml,
20 mM
sodium acetate, 220 mM sucrose, 40 mMNaC1, and 0.02% polysorb ate-20, at pH
5.3. In
another embodiment, provided herein is a composition comprising an anti-TL1A
antibody
provided herein at a concentration of about 100 mg/ml to 200 mg/ml, 20 mM
sodium acetate,
220 mM sucrose, 40 mMNaC1, and 0.02% poly sorb ate-20, at pH 5.3. In another
embodiment, provided herein is a composition comprising an anti-TL1A antibody
provided
herein at a concentration of about 50 mg/ml to 100 mg/ml, 20 mM sodium
phosphate, 5%
sucrose, 85 mM glycine, and 0.02% polysorbate-20, at pH 5.3.
1003011 For various embodiments of the composition provided herein, including
in this
Section (Section 4.5), for example those of the preceding paragraphs), further
embodiments
of the anti-TL1A antibodies, including embodiments with exemplary CDRs,
framework
sequences, constant region sequences, Fc mutations, variable regions, Fc
regions, and other
properties are further provided in Section 4.2; assays for screening, testing,
and validating the
anti-TL1A antibodies are provided in Section 4.3; methods for generating,
improving,
mutating, cloning, expressing, and isolating the anti-TL1A antibodies are
provided in Section
4.4; methods for using the composition are described and provided in Section
4.6; various
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doses or dosing regimen for using the pharmaceutical composition are provided
in Section
4.6 and this Section (Section 4.5); further specific and validated embodiments
for the anti-
TL1A antibodies and the methods of using the same are provided in Section 5.
As such, the
disclosure provides the various combinations of the anti-TL1A antibodies, the
pharmaceutical
compositions of such anti-TL1A antibodies, the doses or the dosing regimens
for using such
pharmaceutical compositions of anti-TL1A antibodies, the methods of generating
the anti-
TL1A antibodies, the methods of assaying the anti-TL1A antibodies, and the
methods of
using the anti-TL1A antibodies for treatment.
4.6 Methods of Treatment
[00302] The disclosure provides that the anti-TL1A antibodies or antigen
binding
fragments and the pharmaceutical compositions thereof provided herein can be
used in a
method to treat an inflammatory disease or condition in a subject by
administering the anti-
TLIA antibodies or antigen binding fragments or the pharmaceutical
compositions thereof
described herein to the subject. More specifically, the anti -TL1 A antibodies
or antigen
binding fragments and the pharmaceutical compositions thereof provided herein
can be used
in a method to treat an inflammatory bowel disease ("IBD") in a subject by
administering the
anti-TL1A antibodies or antigen binding fragments or the pharmaceutical
compositions
thereof described herein to the subject. In various embodiments, IBD is
Crohn's Disease
(CD) and/or ulcerative colitis (UC).
[00303] In one aspect, provided herein is a method of neutralizing monomeric
TL1 A and
trimeric TL1A in a subject comprising (a) administering an effective dose of
anti-TL1A
antibody or antigen binding fragment to the subject, wherein the antibody or
antigen binding
fragment binds to both monomeric TL1A and trimeric TL I A, and wherein the
antibody or
antigen binding fragment blocks interaction of TL1A to DR3. In certain
embodiments, the
subject has IBD. In some embodiments, the concentration of TL1A in a diseased
tissue in the
subject is reduced below the concentration of TL1A in a corresponding tissue
in a control
subject without IBD.
[00304] "Neutralizing" TL1A refers to binding to TL1A in such a way that the
functional
receptor, DR3, can no longer bind to TL and/or signal via the ligation with
TL1A. As
such, an anti-TL1 A antibody that blocks TL1 A binding to DR3 also neutralizes
DR3.
[00305] In another aspect, provided herein is a method of reducing the
concentration of
TL1A in a diseased tissue in a subject with inflammatory bowel disease ("IBD")
comprising
(a) administering an effective dose of anti-TL1A antibody or antigen binding
fragment to the
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subject, thereby reducing the concentration of TLIA in the diseased tissue in
the subject
below the concentration of TLIA in a corresponding tissue in a control subject
without IBD.
[00306] In yet another aspect, provided herein is a method of treating IBD in
a subject in
need thereof comprising (a) administering an anti-TLIA antibody or antigen
binding
fragment to the subject, wherein the anti-TLIA antibody or antigen binding
fragment is
administer at an effective dose such that the concentration of TL1A in a
diseased tissue in the
subject after step (a) is below the concentration of TLIA in a corresponding
tis sue in a
control subject without MD.
[00307] In a further aspect, provided herein is a method of treating IBD in a
subject in
need thereof comprising (a) administering an anti-TLIA antibody or antigen
binding
fragment to the subject, wherein the anti-TL1A antibody or antigen binding
fragment is
administered at an effective dose such that the concentration of TL1A in a
diseased tissue in
the subject after step (a) is below the concentration of TL1 A in a
corresponding tissue in a
control subject without IBD.
[00308] In some embodiments of the various methods provided herein, including
in this
Section (Section 4.6), the diseased tissue comprises or consists of a tissue
in the intestine. In
some embodiments of the various methods provided herein, including in this
Section (Section
4.6), the diseased tissue comprises or consists of 2, 3, 4, 5, 6, 7, 8, or
more tissues in the
intestine. In some embodiments of the various methods provided herein,
including in this
Section (Section 4.6), the corresponding tissue or the reference tissue
comprises or consists of
a tissue in the intestine. In some embodiments of the various methods provided
herein,
including in this Section (Section 4.6), the corresponding tissue or the
reference tissue
comprises or consists of 2, 3,4, 5, 6, 7, 8, or more tissues in the intestine.
[00309] The effective dose used in the methods provided herein, including the
methods
provided in this Section (Section 4.6), can be or include various dosing
regimens. In some
embodiments of the methods provided herein, including the methods provided in
this Section
(Section 4.6), the effective dose comprises an induction regimen. In certain
embodiments,
the effective dose consists of an induction regimen. In some additional
embodiments, the
effective dose comprises a maintenance regimen. In certain further
embodiments, the
effective dose comprises an induction regimen and a maintenance regimen. In
one
embodiment, the effective dose consists of an induction regimen and a
maintenance regimen.
In some other embodiments, the maintenance regimen is administered in a
maintenance step
as further described below.
[00310] The methods provided herein, including in this Section
(Section 4.6), can include
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additional steps. In some embodiments of the methods provided herein,
including the
methods provided in this Section (Section 4.6), the methods further comprises
(c) maintaining
TL1A in the diseased tissue in the subject at a concentration below the
concentration of
TL1A in the corresponding tissue in the control subject. In certain
embodiments, the TL1A
in the diseased tissue in the subject is maintained with a maintenance regimen
of the anti-
TL1A antibody or antigen binding fragment. In some specific embodiments, the
TL1A in the
diseased tissue in the subject is maintained in step (c) with a maintenance
regimen of the anti-
TL1A antibody or antigen binding fragment. In certain embodiments, the
maintenance
regimen is administered after the induction regimen.
1003111 The disclosure provides that the induction regimen and the maintenance
regimen
in the methods provided herein, including in this Section (Section 4.6), can
be identical or
different in various aspects. In one embodiment of the methods provided
herein, including in
this Section (Section 4.6), the induction regimen and the maintenance regimen
are identical.
In another embodiment, the induction regimen and the maintenance regimen are
different. In
a further embodiment, the induction regimen comprises doses of the anti-TL1A
antibody or
antigen binding fragment higher than the maintenance regimen. In yet another
embodiment,
the induction regimen comprises doses of the anti-TL1A antibody or antigen
binding
fragment 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9,
9.5,10, 10.5, 11, 11.5, 12,
12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5,
20, or more fold
higher than the maintenance regimen.
1003121 As described above and below, the various methods provided herein can
reduce
the concentration of TL1A in a diseased tissue in the subject below the
concentration of
TL1A in a corresponding tissue in a control subject without IBD.
Alternatively, the various
methods provided herein can reduce the concentration of TL1A in a diseased
tissue in the
subject below a reference TL1A level (e.g. a reference concentration).
Additionally, the
various methods provided herein can reduce the concentration of TL1A in a
diseased tissue in
the subject below the concentration of TL1A in a reference tissue in a control
subject without
IBD. As is already clear from the description above, the diseased tissue in an
IBD patient
overproduces TL1A, which contributes to the cause, phenotypes, and/or symptoms
of the
IBD patient. The various methods provided herein reduces the concentration of
TL1A in the
diseased tissues of the subject below the concentration of TL1A in a
corresponding tissue in a
control subject without IBD, while the diseased tissues (e.g. certain cells in
the diseased
tissues) of the subject are overproducing TL1A. Such reduction of TL1A
concentration in
the diseased tissues of the subject to below (i) a reference TL1A level or
(ii) the concentration
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of TL in a corresponding tissue or a reference tissue in a control subject
without IBD,
while the diseased tissue in the subject overproduces TL1A, can also be
referred to as
coverage. For example, a coverage of or covering 100 fold overproduction of
TL1A means
that TL1A concentration in the diseased tissues of the subject is reduced to
below the
concentration of TL in a corresponding tissue or a reference tissue in
a control subject
without IBD, while the diseased tissue overproduces TL up to 100 fold
comparing to the
corresponding tissue or the reference tissue in a control subject without IBD.
[00313] Accordingly, in some embodiments of the methods provided herein,
including in
this Section (Section 4.6), the diseased tissue in the subject produces up to
50, up to 55, up to
60, up to 65, up to 70, up to 75, up to 80, up to 85, up to 90, up to 95, up
to 100, up to 105, up
to 110, up to 115, up to 120, up to 125, up to 130, up to 135, up to 140, up
to 145, up to 150,
up to 155, up to 160, up to 165, up to 170, up to 175, up to 180, up to 185,
up to 190, up to
195, up to 200 or up to more fold of TL1A compared to the corresponding tissue
in the
control subject. In certain embodiments, the diseased tissue in the subject
produces about 50,
about 55, about 60, about 65, about 70, about 75, about 80, about 85, about
90, about 95,
about 100, about 105, about 110, about 115, about 120, about 125, about 130,
about 135,
about 140, about 145, about 150, about 155, about 160, about 165, about 170,
about 175,
about 180, about 185, about 190, about 195, about 200 or about more fold of
TL1A compared
to the corresponding tissue in the control subject. In some embodiments, the
diseased tissue
in the subject produces 20 to 50, 20 to 55,20 to 60,20 to 65, 20 to 70,20 to
75,20 to 80,20
to 85, 20 to 90, 20 to 95, 20 to 100, 20 to 105, 20 to 110, 20 to 115, 20 to
120,20 to 125, 20
to 130, 20 to 135, 20 to 140, 20 to 145, 20 to 150,20 to 155, 20to 160, 20to
165, 20 to 170,
20 to 175, 20 to 180, 20 to 185, 20 to 190, 20 to 195, 20 to 200, or more fold
of TL1A
compared to the corresponding tissue in the control subject. In some
embodiments, the
diseased tissue in the subject produces 30 to 50, 30 to 55, 30 to 60, 30 to
65, 30 to 70, 30 to
75,30 to 80,30 to 85,30 to 90,30 to 95,30 to 100, 30 to 105,30 to 110,30 to
115,30 to
120, 30 to 125, 30 to 130, 30 to 135, 30 to 140, 30 to 145, 30 to 150,30 to
155,30 to 160,30
to 165, 30 to 170, 30 to 175, 30 to 180, 30 to 185,30 to 190, 30 to 195, 30 to
200, or more
fold of TL1A compared to the corresponding tissue in the control subject. In
some
embodiments, the diseased tissue in the subject produces 40 to 50,40 to 55, 40
to 60, 40 to
65, 40 to 70, 40 to 75, 40 to 80, 40 to 85, 40 to 90, 40 to 95, 40 to 100, 40
to 105, 40 to 110,
40 to 115, 40 to 120, 40 to 125, 40 to 130, 40 to 135, 40 to 140,40 to 145,40
to 150, 40 to
155, 40 to 160, 40 to 165, 40 to 170, 40 to 175, 40 to 180, 40 to 185,40 to
190,40 to 195,40
to 200, or more fold of TL1A compared to the corresponding tissue in the
control subject. In
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some embodiments, the diseased tissue in the subject produces 50 to 55, 50 to
60, 50 to 65,
50 to 70,50 to 75,50 to 80,50 to 85,50 to 90,50 to 95,50 to 100,50 to 105, 50
to 110,50 to
115, 50 to 120, 50 to 125, 50 to 130, 50 to 135, 50 to 140, 50 to 145,50 to
150,50 to 155,50
to 160, 50 to 165, 50 to 170, 50 to 175, 50 to 180, 50 to 185, 50 to 190, 50
to 195, 50 to 200,
or more fold of TL compared to the corresponding tissue in the control
subject. In some
embodiments, the diseased tissue in the subject produces 60 to 65,60 to 70, 60
to 75,60 to
80, 60 to 85, 60 to 90, 60 to 95, 60 to 100, 60 to 105, 60 to 110,60 to 115,60
to 120, 60to
125, 60 to 130, 60 to 135, 60to 140, 60 to 145, 60 to 150, 60 to 155,60 to
160,60 to 165,60
to 170, 60 to 175, 60 to 180, 60 to 185, 60 to 190,60 to 195, 60 to 200, or
more fold of TLIA
compared to the corresponding tissue in the control subject. In one specific
embodiment, the
diseased tissue in the subject produces up to or about 50 fold of TL1A
compared to the
corresponding tissue in the control subject. In another specific embodiment,
the diseased
tissue in the subject produces up to or about 60 fold of TL1A compared to the
corresponding
tissue in the control subject. In one specific embodiment, the diseased tissue
in the subject
produces up to or about 70 fold of TL1A compared to the corresponding tissue
in the control
subject. In another specific embodiment, the diseased tissue in the subject
produces up to or
about 80 fold of TL1A compared to the corresponding tissue in the control
subject. In one
specific embodiment, the diseased tissue in the subject produces up to or
about 90 fold of
TL1A compared to the corresponding tissue in the control subject. In another
specific
embodiment, the diseased tissue in the subject produces up to or about 100
fold of TL1A
compared to the corresponding tissue in the control subject. In one specific
embodiment, the
diseased tissue in the subject produces up to or about 110 fold of TL1A
compared to the
corresponding tissue in the control subject. In another specific embodiment,
the diseased
tissue in the subject produces up to or about 120 fold of TL1A compared to the
corresponding
tissue in the control subject. In yet another specific embodiment, the
diseased tissue in the
subject produces up to or about 130 fold of TL1A compared to the corresponding
tissue in the
control subject. In a further embodiment, the diseased tissue in the subject
produces up to or
about 140 fold of TL1A compared to the corresponding tissue in the control
subject. In one
embodiment, the diseased tissue in the subject produces up to or about 150
fold of TL1A
compared to the corresponding tissue in the control subject. In another
embodiment, the
diseased tissue in the subject produces up to or about 160 fold of TL1A
compared to the
corresponding tissue in the control subject. In a further embodiment, the
diseased tissue in
the subject produces up to or about 170 fold of TL compared to the
corresponding tissue in
the control subject. In yet another specific embodiment, the diseased tissue
in the subject
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produces up to or about 180 fold of TL1A compared to the corresponding tissue
in the control
subject. In one embodiment, the diseased tissue in the subject produces up to
or about 190
fold of TL1A compared to the corresponding tissue in the control subject. In
another
embodiment, the diseased tissue in the subject produces up to or about 200
fold of TL1A
compared to the corresponding tissue in the control subject. In some
embodiments, the
diseased tissue in the subject overproduces TL1A as described in this
paragraph during the
induction regimen. In some other embodiments, the diseased tissue in the
subject
overproduces TL1A as described in this paragraph before administering the
effective dose.
In certain embodiments, the diseased tissue in the subject overproduces TL1A
as described in
this paragraph within 1, 2, 3, 4, 5, or 6 weeks of start of the induction
regimen. As is clear
from the description, the diseased tissue can overproduce TL via any
combination of the
fold overproduction, timing, and duration as described herein. As is also
clear from the
description above, by providing the reductions of TL1A in the diseased tissue
in this
paragraph with the methods, the disclosure also provides that the method
provided herein can
cover the TL1A over-production, for the fold overproduction, timing and/or
duration, with
the effective dose or induction regimen, as described in this paragraph.
1003141 More specifically, in some embodiments of the methods provided herein,
including in this Section (Section 4.6), the diseased tissue in the subject
produces up to 50, up
to 55, up to 60, up to 65, up to 70, up to 75, up to 80, up to 85, up to 90,
up to 95, up to 100,
up to 105, up to 110, up to 115, up to 120, up to 125, up to 130, up to 135,
up to 140, upto
145, up to 150, up to 155, up to 160, up to 165, up to 170, up to 175, up to
180,up to 185, up
to 190, up to 195, up to 200 or up to more fold of TL1A compared to the
corresponding tissue
in the control subject during the induction regimen. In certain embodiments,
the diseased
tissue in the subject produces about 50, about 55, about 60, about 65, about
70, about 75,
about 80, about 85, about 90, about 95, about 100, about 105, about 110, about
115, about
120, about 125, about 130, about 135, about 140, about 145, about 150, about
155, about 160,
about 165, about 170, about 175, about 180, about 185, about 190, about 195,
about 200 or
about more fold of TLIA compared to the corresponding tissue in the control
subject during
the induction regimen. In some embodiments, the diseased tissue in the subject
produces 20
to 50,20 to 55,20 to 60,20 to 65,20 to 70,20 to 75,20 to 80,20 to 85,20 to 90,
20 to 95,20
to 100, 20 to 105, 20 to 110, 20 to 115, 20 to 120,20 to 125, 20to 130, 20to
135, 20 to 140,
20 to 145, 20 to 150, 20 to 155, 20 to 160, 20 to 165, 20 to 170,20 to 175,20
to 180, 20 to
185, 20 to 190, 20 to 195, 20 to 200, or more fold of TL1A compared to the
corresponding
tissue in the control subject during the induction regimen. In some
embodiments, the
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diseased tissue in the subject produces 30 to 50,30 to 55, 30to 60,30 to 65,
30 to 70, 30to
75, 30 to 80, 30 to 85, 30 to 90, 30 to 95, 30 to 100, 30 to 105, 30 to 110,
30 to 115, 30 to
120, 30to 125, 30to 130, 30to 135, 30 to 140, 30 to 145, 30 to 150,30 to
155,30 to 160, 30
to 165,30 to 170,30 to 175,30 to 180,30 to 185,30 to 190, 30to 195, 30to 200,
or more
fold of TL1A compared to the corresponding tissue in the control subject
during the induction
regimen. In some embodiments, the diseased tissue in the subject produces 40
to 50,40 to
55,40 to 60,40 to 65,40 to 70,40 to 75,40 to 80,40 to 85,40 to 90,40 to 95,40
to 100,40
to 105, 40 to 110, 40 to 115, 40 to 120, 40 to 125,40 to 130, 40to 135, 40to
140, 40 to 145,
40 to 150, 40 to 155, 40 to 160, 40 to 165, 40 to 170, 40 to 175,40 to 180,40
to 185, 40 to
190, 40 to 195, 40 to 200, or more fold of TL1A compared to the corresponding
tissue in the
control subject during the induction regimen. In some embodiments, the
diseased tissue in
the subject produces 50 to 55, 50 to 60, 50 to 65,50 to 70, 50 to 75, 50 to
80,50 to 85, 50 to
90,50 to 95,50 to 100,50 to 105,50 to 110,50 to 115,50 to 120,50 to 125,50 to
130, 50 to
135, 50 to 140, 50 to 145, 50 to 150, 50 to 155, 50 to 160, 50 to 165,50 to
170, 50 to 175,50
to 180, 50 to 185, 50 to 190, 50 to 195, 50 to 200, or more fold of TL1A
compared to the
corresponding tissue in the control subject during the induction regimen. In
some
embodiments, the diseased tissue in the subject produces 60 to 65,60 to 70, 60
to 75, 60 to
80, 60 to 85, 60 to 90, 60 to 95, 60 to 100, 60 to 105, 60 to 110,60 to 115,60
to 120, 60to
125, 60 to 130, 60 to 135, 60 to 140, 60 to 145, 60 to 150, 60 to 155,60 to
160,60 to 165, 60
to 170, 60 to 175, 60 to 180, 60 to 185, 60 to 190, 60 to 195, 60 to 200, or
more fold of TL1A
compared to the corresponding tissue in the control subject during the
induction regimen. In
one specific embodiment, the diseased tissue in the subject produces up to or
about 50 fold of
TL1A compared to the corresponding tissue in the control subject during the
induction
regimen. In another specific embodiment, the diseased tissue in the subject
produces up to or
about 60 fold of TL1A compared to the corresponding tissue in the control
subject during the
induction regimen. In one specific embodiment, the diseased tissue in the
subject produces
up to or about 70 fold of TL1A compared to the corresponding tissue in the
control subject
during the induction regimen. In another specific embodiment, the diseased
tissue in the
subject produces up to or about 80 fold of TL1A compared to the corresponding
tissue in the
control subject during the induction regimen. In one specific embodiment, the
diseased tissue
in the subject produces up to or about 90 fold of TL1A compared to the
corresponding tissue
in the control subject during the induction regimen. In another specific
embodiment, the
diseased tissue in the subject produces up to or about 100 fold of TL1A
compared to the
corresponding tissue in the control subject during the induction regimen. In
one specific
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embodiment, the diseased tissue in the subject produces up to or about 110
fold of TL1A
compared to the corresponding tissue in the control subject during the
induction regimen. In
another specific embodiment, the diseased tissue in the subject produces up to
or about 120
fold of TL1A compared to the corresponding tissue in the control subject
during the induction
regimen. In yet another specific embodiment, the diseased tissue in the
subject produces up
to or about 130 fold of TL1A compared to the corresponding tissue in the
control subject
during the induction regimen. In a further embodiment, the diseased tissue in
the subject
produces up to or about 140 fold of TL1A compared to the corresponding tissue
in the control
subject during the induction regimen. In one embodiment, the diseased tissue
in the subject
produces up to or about 150 fold of TL1A compared to the corresponding tissue
in the control
subject during the induction regimen. In another embodiment, the diseased
tissue in the
subject produces up to or about 160 fold of TL1A compared to the corresponding
tissue in the
control subject during the induction regimen. In a further embodiment, the
diseased tissue in
the subject produces up to or about 170 fold of TL1A compared to the
corresponding tissue in
the control subject during the induction regimen. In yet another specific
embodiment, the
diseased tissue in the subject produces up to or about 180 fold of TL1A
compared to the
corresponding tissue in the control subject during the induction regimen. In
one embodiment,
the diseased tissue in the subject produces up to or about 190 fold of TL1A
compared to the
corresponding tissue in the control subject during the induction regimen. In
another
embodiment, the diseased tissue in the subject produces up to or about 200
fold of TL1A
compared to the corresponding tissue in the control subject during the
induction regimen. As
is clear from the description above, by providing the reductions of TL1A in
the diseased
tissue in this paragraph with the methods, the disclosure also provides that
the method
provided herein can cover the TL1A over-production, for the fold
overproduction, timing
and/or duration, with the effective dose or induction regimen, as described in
this paragraph.
1003151 Similarly, in some embodiments of the methods provided
herein, including in this
Section (Section 4.6), the diseased tissue in the subject produces up to 50,
up to 55, up to 60,
up to 65, up to 70, up to 75, up to 80, up to 85, up to 90, up to 95, up to
100, up to 105, up to
110, up to 115, up to 120, up to 125, up to 130, up to 135, up to 140, up to
145,up to 150, up
to 155, up to 160, up to 165, up to 170, up to 175, up to 180, up to 185, up
to 190, up to 195,
up to 200 or up to more fold of TL1A compared to the corresponding tissue in
the control
subject before the induction regimen. In certain embodiments, the diseased
tissue in the
subject produces about 50, about 55, about 60, about 65, about 70, about 75,
about 80, about
85, about 90, about 95, about 100, about 105, about 110, about 115, about 120,
about 125,
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about 130, about 135, about 140, about 145, about 150, about 155, about 160,
about 165,
about 170, about 175, about 180, about 185, about 190, about 195, about 200 or
about more
fold of TL1A compared to the corresponding tissue in the control subject
before the induction
regimen. In some embodiments, the diseased tissue in the subject produces 20
to 50,20 to
55, 20 to 60, 20 to 65, 20 to 70, 20 to 75, 20 to 80, 20 to 85, 20 to 90,20 to
95, 20 to 100,20
to 105, 20 to 110, 20 to 115, 20 to 120, 20 to 125, 20 to 130, 20to 135, 20to
140, 20 to 145,
20 to 150, 20 to 155, 20 to 160, 20 to 165, 20 to 170, 20 to 175,20 to 180,20
to 185, 20 to
190, 20 to 195, 20 to 200, or more fold of TL1A compared to the corresponding
tissue in the
control subject before the induction regimen. In some embodiments, the
diseased tissue in
the subject produces30 to 50,30 to 55,30 to 60,30 to 65,30 to 70,30 to 75,30
to 80,30 to
85,30 to 90,30 to 95,30 to 100,30 to 105,30 to 110, 30to 115,30 to 120,30 to
125,30 to
130, 30 to 135, 30 to 140, 30 to 145, 30 to 150, 30 to 155, 30 to 160,30 to
165,30 to 170, 30
to 175,30 to 180,30 to 185,30 to 190,30 to 195,30 to 200, or more fold of TL1A
compared
to the corresponding tissue in the control subject before the induction
regimen. In some
embodiments, the diseased tissue in the subject produces 40 to 50,40 to 55, 40
to 60, 40 to
65, 40 to 70, 40 to 75, 40 to 80, 40 to 85, 40 to 90, 40 to 95, 40 to 100, 40
to 105, 40 to 110,
40 to 115, 40 to 120, 40 to 125, 40 to 130, 40 to 135, 40 to 140,40 to 145, 40
to 150, 40 to
155, 40 to 160, 40 to 165, 40 to 170, 40 to 175, 40 to 180, 40 to 185,40 to
190,40 to 195,40
to 200, or more fold of TL1A compared to the corresponding tissue in the
control subject
before the induction regimen. In some embodiments, the diseased tissue in the
subject
produces 50 to 55, 50 to 60,50 to 65, 50 to 70, 50 to 75,50 to 80, 50 to 85,
50 to 90,50 to 95,
50 to 100, 50 to 105, 50 to 110, 50 to 115, 50 to 120, 50 to 125,50 to 130,50
to 135, 50to
140, 50 to 145, 50 to 150, 50 to 155, 50 to 160, 50 to 165, 50 to 170,50 to
175,50 to 180, 50
to 185, 50 to 190, 50 to 195, 50 to 200, or more fold of TL1A compared to the
corresponding
tissue in the control subject before the induction regimen. In some
embodiments, the
diseased tissue in the subject produces 60 to 65, 60 to 70, 60 to 75, 60 to
80,60 to 85, 60 to
90, 60 to 95, 60 to 100, 60 to 105, 60 to 110, 60 to 115, 60 to 120,60 to
125,60 to 130, 60to
135, 60 to 140, 60 to 145, 60 to 150, 60 to 155, 60 to 160, 60 to 165,60 to
170,60 to 175,60
to 180, 60 to 185, 60 to 190, 60 to 195, 60 to 200, or more fold of TL1A
compared to the
corresponding tissue in the control subject before the induction regimen. In
one specific
embodiment, the diseased tissue in the subject produces up to or about 50 fold
of TL1A
compared to the corresponding tissue in the control subject before the
induction regimen. In
another specific embodiment, the diseased tissue in the subject produces up to
or about 60
fold of TL compared to the corresponding tissue in the control
subject before the induction
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regimen. In one specific embodiment, the diseased tissue in the subject
produces up to or
about 70 fold of TL1A compared to the corresponding tissue in the control
subject before the
induction regimen. In another specific embodiment, the diseased tissue in the
subject
produces up to or about 80 fold of TL1A compared to the corresponding tissue
in the control
subject before the induction regimen. In one specific emb odiment, the
diseased tissue in the
subject produces up to or about 90 fold of TL compared to the corresponding
tissue in the
control subject before the induction regimen. In another specific embodiment,
the diseased
tissue in the subject produces up to or about 100 fold of TL1A compared to the
corresponding
tissue in the control subject before the induction regimen. In one specific
embodiment, the
diseased tissue in the subject produces up to or about 110 fold of TL1A
compared to the
corresponding tissue in the control subject before the induction regimen. In
another specific
embodiment, the diseased tissue in the subject produces up to or about 120
fold of TL1A
compared to the corresponding tissue in the control subject before the
induction regimen. In
yet another specific embodiment, the diseased tissue in the subject produces
up to or about
130 fold of TL1A compared to the corresponding tissue in the control subject
before the
induction regimen. In a further embodiment, the diseased tissue in the subject
produces up to
or about 140 fold of TL compared to the corresponding tissue in the control
subject before
the induction regimen. In one embodiment, the diseased tissue in the subject
produces up to
or about 150 fold of TL compared to the corresponding tissue in the control
subject before
the induction regimen. In another embodiment, the diseased tissue in the
subject produces up
to or about 160 fold of TL1A compared to the corresponding tissue in the
control subject
before the induction regimen. In a further embodiment, the diseased tissue in
the subject
produces up to or about 170 fold of TL1A compared to the corresponding tissue
in the control
subject before the induction regimen. In yet another specific embodiment, the
diseased tissue
in the subject produces up to or about 180 fold of TL1A compared to the
corresponding tissue
in the control subject before the induction regimen. In one embodiment, the
diseased tissue
in the subject produces up to or about 190 fold of TL1A compared to the
corresponding tissue
in the control subject before the induction regimen. In another embodiment,
the diseased
tissue in the subject produces up to or about 200 fold of TL1A compared to the
corresponding
tissue in the control subject before the induction regimen. As is clear from
the description
above, by providing the reductions of TL1A in the diseased tissue in this
paragraph with the
methods, the disclosure also provides that the method provided herein can
cover the TL1A
over-production, for the fold overproduction, timing and/or duration, with the
effective dose
or induction regimen, as described in this paragraph.
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1003161 Alternatively, in some embodiments of the methods provided herein,
including in
this Section (Section 4.6), the diseased tissue in the subject produces up to
50, up to 55, up to
60, up to 65, up to 70, up to 75, up to 80, up to 85, up to 90, up to 95, up
to 100, up to 105, up
to 110, up to 115, up to 120, up to 125, up to 130,up to 135, up to 140, upto
145, up to 150,
up to 155, up to 160, up to 165, up to 170, up to 175, up to 180, up to 185,
up to 190, up to
195, up to 200 or up to more fold of TL1A compared to the corresponding tissue
in the
control subject within 1, 2, 3, 4, 5, or 6 weeks of the start of the induction
regimen. In certain
embodiments, the diseased tissue in the subject produces about 50, about 55,
about 60, about
65, about 70, about 75, about 80, about 85, about 90, about 95, about 100,
about 105, about
110, about 115, about 120, about 125, about 130, about 135, about 140, about
145, about 150,
about 155, about 160, about 165, about 170, about 175, about 180, about 185,
about 190,
about 195, about 200 or about more fold of TL1A compared to the corresponding
tissue in
the control subject within 1, 2, 3, 4, 5, or 6 weeks of the start of the
induction regimen In
some embodiments, the diseased tissue in the subject produces 20 to 50,20 to
55, 20 to 60,
20 to 65, 20 to 70, 20 to 75, 20 to 80, 20 to 85, 20 to 90, 20 to 95, 20 to
100, 20 to 105,20 to
110, 20 to 115, 20 to 120, 20 to 125, 20 to 130, 20 to 135, 20 to 140, 20 to
145,20 to 150,20
to 155, 20 to 160, 20 to 165, 20 to 170, 20 to 175,20 to 180, 20to 185, 20to
190, 20 to 195,
20 to 200, or more fold of TL1A compared to the corresponding tissue in the
control subject
within 1, 2, 3, 4, 5, or 6 weeks of the start of the induction regimen. In
some embodiments,
the diseased tissue in the subject produces 30 to 50, 30 to 55, 30 to 60,30 to
65, 30 to 70, 30
to 75, 30 to 80, 30 to 85,30 to 90, 30 to 95, 30 to 100, 30 to 105, 30 to
110,30 to 115, 30 to
120, 30 to 125, 30 to 130, 30to 135, 30 to 140, 30 to 145, 30 to 150,30 to
155,30 to 160,30
to 165, 30 to 170, 30 to 175, 30 to 180, 30 to 185,30 to 190, 30 to 195, 30 to
200, or more
fold of 'TL1A compared to the corresponding tissue in the control subject
within 1, 2, 3, 4, 5,
or 6 weeks of the start of the induction regimen. In some embodiments, the
diseased tissue in
the subject produces40 to 50, 40 to 55, 40 to 60,40 to 65, 40 to 70, 40 to
75,40 to 80, 40 to
85, 40 to 90, 40 to 95, 40 to 100, 40 to 105,40 to 110, 40 to 115, 40 to 120,
40 to 125, 40 to
130, 40 to 135, 40 to 140, 40 to 145, 40 to 150, 40 to 155, 40 to 160,40 to
165,40 to 170,40
to 175, 40 to 180, 40 to 185, 40 to 190, 40 to 195,40 to 200, or more fold of
TL1A compared
to the corresponding tissue in the control subject within 1, 2, 3, 4, 5, or 6
weeks of the start of
the induction regimen. In some embodiments, the diseased tissue in the subject
produces 50
to 55,50 to 60, 50 to 65,50 to 70, 50 to 75,50 to 80,50 to 85,50 to 90,50 to
95, 50 to 100,
50 to 105,50 to 110,50 to 115,50 to 120,50 to 125,50 to 130,50 to 135,50 to
140, 50 to
145, 50 to 150, 50 to 155, 50 to 160, 50 to 165, 50 to 170, 50 to 175,50 to
180,50 to 185, 50
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to 190, 50 to 195, 50 to 200, or more fold of TL1A compared to the
corresponding tissue in
the control subject within 1, 2, 3, 4, 5, or 6 weeks of the start of the
induction regimen. In
some embodiments, the diseased tissue in the subject produces 60 to 65,60 to
70, 60 to 75,
60 to 80,60 to 85,60 to 90,60 to 95,60 to 100,60 to 105,60 to 110,60 to 115,
60 to 120,60
to 125,60 to 130,60 to 135,60 to 140,60 to 145,60 to 150, 60 to 155, 60 to
160,60 to 165,
60 to 170, 60 to 175, 60 to 180, 60 to 185, 60 to 190, 60 to 195,60 to 200, or
more fold of
TL1A compared to the corresponding tissue in the control subject within 1, 2,
3, 4, 5, or 6
weeks of the start of the induction regimen. In one specific embodiment, the
diseased tissue
in the subject produces up to or about 50 fold of TL1A compared to the
corresponding tissue
in the control subject within 1, 2, 3, 4, 5, or 6 weeks of the start of the
induction regimen. In
another specific embodiment, the diseased tissue in the subject produces up to
or about 60
fold of TL compared to the corresponding tissue in the control
subject within 1, 2, 3, 4, 5,
or 6 weeks of the start of the induction regimen. In one specific embodiment,
the diseased
tissue in the subject produces up to or about 70 fold of TL1A compared to the
corresponding
tissue in the control subject within 1, 2, 3, 4, 5, or 6 weeks of the start of
the induction
regimen. In another specific embodiment, the diseased tissue in the subject
produces up to or
about 80 fold of TL1A compared to the corresponding tissue in the control subj
ect within 1,
2, 3, 4, 5, or 6 weeks of the start of the induction regimen. In one specific
embodiment, the
diseased tissue in the subject produces up to or about 90 fold of TL1A
compared to the
corresponding tissue in the control subject within 1, 2, 3, 4, 5, or 6 weeks
of the start of the
induction regimen. In another specific embodiment, the diseased tissue in the
subject
produces up to or about 100 fold of TL1A compared to the corresponding tissue
in the control
subject within 1, 2, 3, 4, 5, or 6 weeks of the start of the induction
regimen. In one specific
embodiment, the diseased tissue in the subject produces up to or about 110
fold of TL1A
compared to the corresponding tissue in the control subject within 1, 2, 3, 4,
5, or 6 weeks of
the start of the induction regimen. In another specific embodiment, the
diseased tissue in the
subject produces up to or about 120 fold of TL1A compared to the corresponding
tissue in the
control subject within 1, 2, 3, 4, 5, or 6 weeks of the start of the induction
regimen. In yet
another specific embodiment, the diseased tissue in the subject produces up to
or about 130
fold of TL1A compared to the corresponding tissue in the control subject
within 1, 2, 3, 4, 5,
or 6 weeks of the start of the induction regimen. In a further embodiment, the
diseased tissue
in the subject produces up to or about 140 fold of TL1A compared to the
corresponding tissue
in the control subject within 1, 2, 3, 4, 5, or 6 weeks of the start of the
induction regimen. In
one embodiment, the diseased tissue in the subject produces up to or about 150
fold of TL1A
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compared to the corresponding tissue in the control subject within 1, 2, 3, 4,
5, or 6 weeks of
the start of the induction regimen. In another embodiment, the diseased tissue
in the subject
produces up to or about 160 fold of TL1A compared to the corresponding tissue
in the control
subject within 1, 2, 3, 4, 5, or 6 weeks of the start of the induction
regimen. In a further
embodiment, the diseased tissue in the subject produces up to or about 170
fold of TL1A
compared to the corresponding tissue in the control subject within 1, 2, 3, 4,
5, or 6 weeks of
the start of the induction regimen. In yet another specific embodiment, the
diseased tissue in
the subject produces up to or about 180 fold of TLIA compared to the
corresponding tissue in
the control subject within 1, 2, 3, 4, 5, or 6 weeks of the start of the
induction regimen. In
one embodiment, the diseased tissue in the subject produces up to or about 190
fold of TLIA
compared to the corresponding tissue in the control subject within 1,2, 3,4,
5, or 6 weeks of
the start of the induction regimen. In another embodiment, the diseased tissue
in the subject
produces up to or about 200 fold of TL1A compared to the corresponding tissue
in the control
subject within 1, 2, 3, 4, 5, or 6 weeks of the start of the induction
regimen. As is clear from
the description above, by providing the reductions of TL1A in the diseased
tissue in this
paragraph with the methods, the disclosure also provides that the method
provided herein can
cover the TL I A over-production, for the fold overproduction, timing and/or
duration, with
the effective dose or induction regimen, as described in this paragraph.
1003171 The induction regimen can comprise one or more administrations of the
anti-
TLIA antibody or antigen binding fragment to reduce the concentration of TLIA
in a
diseased tissue in the subject. In one embodiment of the methods provided
herein, including
in this Section (Section 4.6), the induction regimen comprises a one-time
administration of
the anti-TLIA antibody or antigen binding fragment. In some embodiments, the
induction
regimen comprises a one-time administration of the anti-TL1A antibody or
antigen binding
fragment at about 150 mg/dose. In one embodiment, the induction regimen
comprises a one-
time administration of the anti-TL1A antibody or antigen binding fragment at
about 200
mg/dose. In another embodiment, the induction regimen comprises a one-time
administration
of the anti-TL1A antibody or antigen binding fragment at about 250 mg/dose. In
a further
embodiment, the induction regimen comprises a one-time administration of the
anti-TLIA
antibody or antigen binding fragment at about 300 mg/dose. In yet another
embodiment, the
induction regimen comprises a one-time administration of the anti-TLIA
antibody or antigen
binding fragment at about 350 mg/dose In one embodiment, the induction regimen
comprises a one-time administration of the anti-TL1A antibody or antigen
binding fragment
at about 400 mg/dose. In another embodiment, the induction regimen comprises a
one-time
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administration of the anti-TL1A antibody or antigen binding fragment at about
450 mg/dose.
In yet another embodiment, the induction regimen comprises a one-time
administration of the
anti-TL1A antibody or antigen binding fragment at about 500 mg/dose. In one
embodiment,
the induction regimen comprises a one-time administration of the anti-TL1A
antibody or
antigen binding fragment at about 550 mg/dose. In yet another embodiment, the
induction
regimen comprises a one-time administration of the anti-TL1A antibody or
antigen binding
fragment at about 600 mg/dose. In another embodiment, the induction regimen
comprises a
one-time administration of the anti-TL1A antibody or antigen binding fragment
at about 650
mg/dose. In a further embodiment, the induction regimen comprises a one-time
administration of the anti-TL1A antibody or antigen binding fragment at about
700 mg/dose.
In one embodiment, the induction regimen comprises a one-time administration
of the anti-
TL1A antibody or antigen binding fragment at about 750 mg/dose. In another
embodiment,
the induction regimen comprises a one-time administration of the anti-TL1A
antibody or
antigen binding fragment at about 800 mg/dose. In one embodiment, the
induction regimen
comprises a one-time administration of the anti-TL1A antibody or antigen
binding fragment
at about 850 mg/dose. In a further embodiment, the induction regimen comprises
a one-time
administration of the anti-TL1A antibody or antigen binding fragment at about
900 mg/dose.
In one embodiment, the induction regimen comprises a one-time administration
of the anti-
TL1A antibody or antigen binding fragment at about 950 mg/dose. In yet another
embodiment, the induction regimen comprises a one-time administration of the
anti-TL1A
antibody or antigen binding fragment at about 1000 mg/dose. In yet another
embodiment, the
induction regimen comprises a one-time administration of the anti-TL1A
antibody or antigen
binding fragment at about 1100 mg/dose. In one embodiment, the induction
regimen
comprises a one-time administration of the anti-TL1A antibody or antigen
binding fragment
at about 1200 mg/dose. In another embodiment, the induction regimen comprises
a one-time
administration of the anti-TL1A antibody or antigen binding fragment at about
1250
mg/dose. In a further embodiment, the induction regimen comprises a one-time
administration of the anti-TL1A antibody or antigen binding fragment at about
1300
mg/dose. In yet another embodiment, the induction regimen comprises a one-time
administration of the anti-TL1A antibody or antigen binding fragment at about
1400
mg/dose. In yet another embodiment, the induction regimen comprises a one-time
administration of the anti-TL1A antibody or antigen binding fragment at about
1500
mg/dose. In one embodiment, the induction regimen comprises a one-time
administration of
the anti-TL1A antibody or antigen binding fragment at about 1600 mg/dose. In
another
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embodiment, the induction regimen comprises a one-time administration of the
anti-TLIA
antibody or antigen binding fragment at about 1700 mg/dose. In a further
embodiment, the
induction regimen comprises a one-time administration of the anti-TLIA
antibody or antigen
binding fragment at about 1750 mg/dose. In yet another embodiment, the
induction regimen
comprises a one-time administration of the anti-TLIA antibody or antigen
binding fragment
at about 1800 mg/dose. In yet another embodiment, the induction regimen
comprises a one-
time administration of the anti-TL I A antibody or antigen binding fragment at
about 1900
mg/dose. In one embodiment, the induction regimen comprises a one-time
administration of
the anti-TL I A antibody or antigen binding fragment at about 2000 mg/dose.
1003181 Alternatively, the induction regimen can comprise multiple
administrations of the
anti-TL1A antibody or antigen binding fragment. In one embodiment, the
induction regimen
comprises 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14,15, 16,17, 18,19, 20, or
more
administrations the anti-TLIA antibody or antigen binding fragments. In
another
embodiment, the induction regimen comprises administration of about 2000,
1950, 1900,
1850, 1800, 1750, 1700, 1650, 1600, 1550, 1500, 1450, 1400, 1350, 1300,1250,
1200, 1150,
1000, 950, 900, 850, 800, 750, 700, 650, 600, 550, 500, 450, 400, 350, 300,
250, 200, or 150
mg/dose. In one embodiment, the induction regimen comprises administration of
200 to
2000, 200 to 1950, 200to 1900, 200to 1850,200 to 1800,200 to 1750, 200 to
1700, 200to
1650, 200 to 1600, 200to 1550, 200to 1500,200 to 1450,200 to 1400, 200to 1350,
200to
1300, 200 to 1250, 200to 1200, 200to 1150,200 to 1000,200 to 950, 200to 900,
200to
850, 200 to 800, 200 to 750, 200 to 700,200 to 650, 200 to 600, 200 to 550,200
to 500, 200
to 450, 200 to 400, 200 to 350, 200to 300, or 200 to 250 mg/dose. In one
embodiment, the
induction regimen comprises administration of 100 to 2000, 100 to 1950, 100 to
1900, 100 to
1850, 100 to 1800, 100 to 1750, 100 to 1700, 100 to 1650, 100 to 1600, 100 to
1550, 100 to
1500, 100 to 1450, 100 to 1400, 100 to 1350,100 to 1300,100 to 1250, 100 to
1200, 100to
1150, 100 to 1000, 100 to 950, 100 to 900,100 to 850, 100 to 800, 100 to
750,100 to 700,
100 to 650, 100 to 600, 100 to 550, 100 to 500, 1 00 to 450, 100 to 400, 100
to 350, 100 to
300, or 100 to 250 mg/dose. In one embodiment, the induction regimen comprises
administration of 300 to 2000, 300 to 1950, 300 to 1900,300 to 1850, 300 to
1800, 300 to
1750, 300 to 1700, 300 to 1650, 300 to 1600, 300 to 1550,300 to 1500, 300 to
1450, 300 to
1400, 300 to 1350, 300 to 1300, 300to 1250,300 to 1200,300 to 1150, 300 to
1000, 300 to
950, 300 to 900, 300 to 850, 300 to 800,300 to 750, 300 to 700, 300 to 650,300
to 600, 300
to 550, 300 to 500, 300 to 450, 300 to 400, or 300 to 350 mg/dose. In yet
another
embodiment, the induction regimen comprises administration once every 1,2,
3,4, 5, 6,7, or
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8 weeks. In a further embodiment, the induction regimen comprises
administration once
every 1,2, 3 or 4 weeks for the first 2 administrations and then once every
1,2, 3,4, 5,6, 7,
or 8 weeks for the remaining induction regimen. In one embodiment, the
induction regimen
comprises administration week 0 and week 2 for the first 2 administrations and
then once
every 1, 2, 3, 4, 5, 6, 7, or 8 weeks for the remaining induction regimen. In
another
embodiment, the duration of the induction regimen is shorter than the duration
of the
maintenance regimen. In a further embodiment, the induction regimen continues
for 6, 7, 8,
9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19,20, or more weeks. The disclosure
further provides
that the induction regimen can comprise any combination of the dosing amount,
dosing
frequency, number of administrations, and/or the duration of the induction
regimen.
Accordingly and as an example, in some embodiments, the induction regimen can
comprise
administration of about 2000, 1950, 1900, 1850, 1800, 1750, 1700, 1650, 1600,
1550, 1500,
1450, 1400, 1350, 1300, 1250, 1200, 1150, 1000, 950, 900, 850, 800, 750, 700,
650, 600,
550, 500, 450, 400,350,300, 250, or 200 mg/dose for administrations at week 0
and week 2
for the first 2 administrations and then once every 2, 3, 4, 5, 6, 7, or 8
weeks, fora duration of
6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more weeks for the
induction regimen.
Similarly, in some embodiments, the induction regimen can comprise
administration of about
2000, 1950, 1900, 1850, 1800, 1750, 1700, 1650, 1600, 1550, 1500, 1450,1400,
1350, 1300,
1250, 1200, 1150, 1000,950, 900,850,800,750, 700,650, 600, 550, 500,450,400,
350,
300, 250, or 200 mg/dose for administrations at week 0 and week 2 for the
first 2
administrations and then administration of about 1500, 1450, 1400, 1350, 1300,
1250, 1200,
1150, 1000,950,900,850,800,750,700, 650, 600, 550,500,450,400,350,
300,250,200,
or 150 mg/dose once every 2, 3, 4, 5, 6, 7, or 8 weeks, for a duration of 6,
7, 8, 9, 10, 11, 12,
13, 14, 15, 16, 17, 18, 19, 20, or more weeks for the induction regimen.
[00319] Specifically, in some embodiments, the induction regimen
comprises
administrations of about 1000 mg/dose on week 0, about 1000 mg/dose on week 2,
about
1000 mg/dose on week 6, and about 1000 mg/dose on week 10. In some
embodiments, the
induction regimen comprises administrations of about 500 mg/dose on week 0,
about 500
mg/dose on week 2, about 500 mg/dose on week 6, and about 500 mg/dose on week
10. In
some embodiments, the induction regimen comprises administrations of about
1000 mg/dose
on week 0, about 1000 mg/dose on week 2, about 1000 mg/dose on week 6, and
about 500
mg/dose on week 10. In some embodiments, the induction regimen comprises
administrations of about 1000 mg/dose on week 0, about 1000 mg/dose on week 2,
about 500
mg/dose on week 6, and about 500 mg/dose on week 10. In some embodiments, the
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induction regimen comprises administrations of about 1000 mg/dose on week 0,
about 500
mg/dose on week 2, about 500 mg/dose on week 6, and about 500 mg/dose on week
10. In
some embodiments, the induction regimen comprises administrations of about 750
mg/dose
on week 0, about 750 mg/dose on week 2, about 750 mg/dose on week 6, and about
750
mg/dose on week 10. In some embodiments, the induction regimen comprises
administrations of about 500 mg/dose on week 0, about 500 mg/dose on week 2,
about 500
mg/dose on week 6, and about 500 mg/dose on week 10. In some embodiments, the
induction regimen comprises administrations of about 750 mg/dose on week 0,
about 750
mg/dose on week 2, about 750 mg/dose on week 6, and about 500 mg/dose on week
10. In
some embodiments, the induction regimen comprises administrations of about 750
mg/dose
on week 0, about 750 mg/dose on week 2, about 500 mg/dose on week 6, and about
500
mg/dose on week 10. In some embodiments, the induction regimen comprises
administrations of about 750 mg/dose on week 0, about 500 mg/dose on week 2,
about 500
mg/dose on week 6, and about 500 mg/dose on week 10. In some embodiments, the
induction regimen comprises administrations of about 1500 mg/dose on week 0,
about 1500
mg/dose on week 2, about 1500 mg/dose on week 6, and about 1500 mg/dose on
week 10. In
some embodiments, the induction regimen comprises administrations of about 500
mg/dose
on week 0, about 500 mg/dose on week 2, about 500 mg/dose on week 6, and about
500
mg/dose on week 10. In some embodiments, the induction regimen comprises
administrations of about 1500 mg/dose on week 0, about 1500 mg/dose on week 2,
about
1500 mg/dose on week 6, and about 500 mg/dose on week 10. In some embodiments,
the
induction regimen comprises administrations of about 1500 mg/dose on week 0,
about 1500
mg/dose on week 2, about 500 mg/dose on week 6, and about 500 mg/dose on week
10. In
some embodiments, the induction regimen comprises administrations of about
1500 mg/dose
on week 0, about 500 mg/dose on week 2, about 500 mg/dose on week 6, and about
500
mg/dose on week 10. In some embodiments, the induction regimen comprises
administrations of about 750 mg/dose on week 0, about 750 mg/dose on week 2,
about 750
mg/dose on week 6, and about 750 mg/dose on week 10. In some embodiments, the
induction regimen comprises administrations of about 1000 mg/dose on week 0,
about 1000
mg/dose on week 2, about 1000 mg/dose on week 6, and about 750 mg/dose on week
10. In
some embodiments, the induction regimen comprises administrations of about
1000 mg/dose
on week 0, about 1000 mg/dose on week 2, about 750 mg/dose on week 6, and
about 750
mg/dose on week 10. In some embodiments, the induction regimen comprises
administrations of about 1000 mg/dose on week 0, about 750 mg/dose on week 2,
about 750
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mg/dose on week 6, and about 750 mg/dose on week 10. In some embodiments, the
induction regimen comprises administrations of about 1500 mg/dose on week 0,
about 1500
mg/dose on week 2, about 1500 mg/dose on week 6, and about 1500 mg/dose on
week 10. In
some embodiments, the induction regimen comprises administrations of about 750
mg/dose
on week 0, about 750 mg/dose on week 2, about 750 mg/dose on week 6, and about
750
mg/dose on week 10. In some embodiments, the induction regimen comprises
administrations of about 1500 mg/dose on week 0, about 1500 mg/dose on week 2,
about
1500 mg/dose on week 6, and about 750 mg/dose on week 10. In some embodiments,
the
induction regimen comprises administrations of about 1500 mg/dose on week 0,
about 1500
mg/dose on week 2, about 750 mg/dose on week 6, and about 750 mg/dose on week
10. In
some embodiments, the induction regimen comprises administrations of about
1500 mg/dose
on week 0, about 750 mg/dose on week 2, about 750 mg/dose on week 6, and about
750
mg/dose on week 10.
[00320] In one embodiment, the duration of the induction regimen is shorter
than the
duration of the maintenance regimen. In a further embodiment, the induction
regimen
continues for 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. In
another
embodiment, the induction regimen continues for 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, or 12 weeks. In
yet another embodiment, the induction regimen continues for 8 weeks. In one
embodiment,
the induction regimen continues for 9 weeks. In one embodiment, the induction
regimen
continues for 10 weeks. In one embodiment, the induction regimen continues for
11 weeks.
In one embodiment, the induction regimen continues for 12 weeks.
[00321] As used herein, week 0 means day 1 of the administration of the anti-
TL1A
antibody or antigen binding fragments. Week 0 of the induction regimen means
day 1 of the
administration of the anti-TL1A antibody or antigen binding fragments in the
induction
regimen. Week 0 of the maintenance regimen means day 1 of the administration
of the anti-
TL1A antibody or antigen binding fragments in the maintenance regimen.
[00322] The disclosure provides that the diseased tissue in the
subject can overproduce
and/or continue to overproduce (e.g. cells in the diseased tissue
overexpresses) TL1A after
the induction regimen. Thus, in some embodiments, the disclosure further
provides a
maintenance regimen for the various methods provided herein to maintain the
TL1A in the
diseased tissue in the subject at a concentration below the concentration of
TL in the
corresponding tissue in the control subject without1BD. In certain
embodiments, the
methods provided herein further comprise a maintenance regimen to maintain the
TL1A in
the diseased tissue in the subject at a concentration below the concentration
of IL in a
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reference tissue in the control subject without IBD. In some other
embodiments, the methods
provided herein further comprise a maintenance regimen to maintain the TL1A in
the
diseased tissue in the subject at a concentration below a reference TL1A level
(e.g. a
reference concentration).
1003231 As described herein, the concentration of TL1A in the diseased tissue
of the
subject is reduced below (i) a reference TL level or (ii) the concentration
of TL in a
corresponding tissue or a reference tissue in in a control subject without
IBD, while the
diseased tissues (e.g. certain cells in the diseased tissues) of the subject
overproduces TL1A.
Accordingly, the reduction of the TL1A in the diseased tissue can be
maintained at or during
any or all time of the maintenance regimen, while the diseased tissues (e.g.
certain cells in the
diseased tissues) of the subject overproduces TL1A at various level of
overproduction. In
some embodiments of the methods provided herein, including in this Section
(Section 4.6),
the diseased tissue in the subject produces up to 10, up to 15, up to 20, up
to 25, up to 30, up
to 35, up to 40, up to 45, up to 50, up to 55, up to 60, up to 65, up to 70,
up to 75, up to 80, up
to 85, up to 90, up to 95, up to 100, or up to more fold of TLIA compared to
the
corresponding tissue in the control subject during the maintenance regimen. In
certain
embodiments, the diseased tissue in the subject produces about 10, about 15,
about 20, about
25, about 30, about 35, about 40, about 45, about 50, about 50, about 55,
about 60, about 65,
about 70, about 75, about 80, about 85, about 90, about 95, about 100, or
about more fold of
TL1A compared to the corresponding tissue in the control subject during the
maintenance
regimen. In some embodiments, the diseased tissue in the subject produces 10
to 15, 10 to
20, 10 to 25, 10 to 30, 10 to 35, 10 to 40, 10 to 45, 10 to 50, 10 to 50,10 to
55, 10 to 60, 10 to
65, 10 to 70, 10 to 75, 10 to 80, 10 to 85, 10 to 90, 10 to 95, 10 to 100 fold
of TLIA
compared to the corresponding tissue in the control subject during the
maintenance regimen.
In some embodiments, the diseased tissue in the subject produces 20 to 25, 20
to 30, 20 to 35,
20 to 40, 20 to 45, 20 to 50, 20 to 50, 20 to 55, 20 to 60, 20 to 65, 20 to
70, 20 to 75, 20 to 80,
20 to 85, 20 to 90, 20 to 95, 20 to 100 fold of TL1A compared to the
corresponding tissue in
the control subject during the maintenance regimen. In some embodiments, the
diseased
tissue in the subject produces 30 to 35,30 to 40, 30 to 45, 30 to 50,30 to 50,
30 to 55,30 to
60, 30 to 65, 30 to 70, 30 to 75, 30 to 80, 30 to 85, 30 to 90, 30 to 95,30 to
100 fold of TLIA
compared to the corresponding tissue in the control subject during the
maintenance regimen.
In some embodiments, the diseased tissue in the subject produces 40 to 45, 40
to 50, 40 to 50,
40 to 55,40 to 60,40 to 65,40 to 70,40 to 75,40 to 80,40 to 85,40 to 90, 40 to
95,40 to
100 fold of TL1A compared to the corresponding tissue in the control subject
during the
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maintenance regimen. In some embodiments, the diseased tissue in the subject
produces 50
to 55, 50 to 60, 50 to 65,50 to 70, 50 to 75, 50 to 80, 50 to 85, 50 to 90, 50
to 95, 50 to 100
fold of TLIA compared to the corresponding tissue in the control subject
during the
maintenance regimen. In one embodiment, the diseased tissue in the subject
produces up to
or about 10 fold of TLIA compared to the corresponding tissue in the control
subject during
the maintenance regimen. In another embodiment, the diseased tissue in the
subject produces
up to or about 20 fold of TL1A compared to the corresponding tissue in the
control subject
during the maintenance regimen. In another embodiment, the diseased tissue in
the subject
produces up to or about 30 fold of TL1A compared to the corresponding tissue
in the control
subject during the maintenance regimen. In another embodiment, the diseased
tissue in the
subject produces up to or about 40 fold of TLIA compared to the corresponding
tissue in the
control subject during the maintenance regimen. In one specific embodiment,
the diseased
tissue in the subject produces up to or about 50 fold of TLIA compared to the
corresponding
tissue in the control subject during the maintenance regimen. In another
specific
embodiment, the diseased tissue in the subject produces up to or about 60 fold
of TLI A
compared to the corresponding tissue in the control subject during the
maintenance regimen.
In one specific embodiment, the diseased tissue in the subject produces up to
or about 70 fold
of TLIA compared to the corresponding tissue in the control subject during the
maintenance
regimen. In another specific embodiment, the diseased tissue in the subject
produces up to or
about 80 fold of TLIA compared to the corresponding tissue in the control
subject during the
maintenance regimen. In one specific embodiment, the diseased tissue in the
subject
produces up to or about 90 fold of TLIA compared to the corresponding tissue
in the control
subject during the maintenance regimen. In another specific embodiment, the
diseased tissue
in the subject produces up to or about 100 fold of TL1A compared to the
corresponding tissue
in the control subject during the maintenance regimen. In one embodiment, the
diseased
tissue in the subject produces up to or about 110 fold of TLIA compared to the
corresponding
tissue in the control subject during the maintenance regimen. In another
embodiment, the
diseased tissue in the subject produces up to or about 120 fold of TL 1A
compared to the
corresponding tissue in the control subject during the maintenance regimen. As
is clear from
the description above, by providing the reductions of TLIA in the diseased
tissue in this
paragraph with the methods, the disclosure also provides that the method
provided herein can
cover the TLIA over-production, for the fold overproduction, timing and/or
duration, with
the effective dose or maintenance regimen, as described in this paragraph.
[00324] Similarly, in some embodiments of the methods provided
herein, including in this
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Section (Section 4.6), the diseased tissue in the subject produces up to 10,
up to 15, up to 20,
up to 25, up to 30, up to 35, up to 40, up to 45, up to 50, up to 55, up to
60, up to 65, up to 70,
up to 75, up to 80, up to 85, up to 90, up to 95, up to 100, or up to more
fold of TL1A
compared to the corresponding tissue in the control subject before the
maintenance regimen.
In certain embodiments, the diseased tissue in the subject produces about 10,
about 15, about
20, about 25, about 30, about 35, about 40, about 45, about 50, about 55,
about 60, about 65,
about 70, about 75, about 80, about 85, about 90, about 95, about 100 or about
more fold of
TL1A compared to the corresponding tissue in the control subject before the
maintenance
regimen. In some embodiments, the diseased tissue in the subject produces 10
to 15, 10 to
20, 10 to 25, 10 to 30, 10 to 35, 10 to 40, 10 to 45, 10 to 50, 10 to 50, 10
to 55, 10 to 60, 10 to
65, 10 to 70, 10 to 75, 10 to 80, 10 to 85, 10 to 90, 10 to 95, 10 to 100 fold
of TL1A
compared to the corresponding tissue in the control subject before the
maintenance regimen.
In some embodiments, the diseased tissue in the subject produces 20 to 25,20
to 30,20 to 35,
20 to 40, 20 to 45, 20 to 50, 20 to 50, 20 to 55, 20 to 60, 20 to 65, 20 to
70, 20 to 75, 20 to 80,
20 to 85, 20 to 90, 20 to 95, 20 to 100 fold of TL1A compared to the
corresponding tissue in
the control subject before the maintenance regimen. In some embodiments, the
diseased
tissue in the subject produces 30 to 35,30 to 40,30 to 45, 30 to 50,30 to 50,
30 to 55,30 to
60, 30 to 65,30 to 70, 30 to 75,30 to 80,30 to 85,30 to 90,30 to 95,30 to 100
fold of TL1A
compared to the corresponding tissue in the control subject before the
maintenance regimen.
In some embodiments, the diseased tissue in the subject produces 40 to 45, 40
to 50, 40 to 50,
40 to 55,40 to 60,40 to 65,40 to 70,40 to 75,40 to 80,40 to 85,40 to 90, 40 to
95,40 to
100 fold of TL1A compared to the corresponding tissue in the control subject
before the
maintenance regimen. In some embodiments, the diseased tissue in the subject
produces 50
to 55, 50 to 60, 50 to 65, 50 to 70, 50 to 75, 50 to 80, 50 to 85, 50 to 90,
50 to 95, 50 to 100
fold of TL1A compared to the corresponding tissue in the control subject
before the
maintenance regimen. In one specific embodiment, the diseased tissue in the
subject
produces up to or about 10 fold of TL1A compared to the corresponding tissue
in the control
subject before the maintenance regimen. In one specific embodiment, the
diseased tissue in
the subject produces up to or about 20 fold of TL1A compared to the
corresponding tissue in
the control subject before the maintenance regimen. In one specific
embodiment, the
diseased tissue in the subject produces up to or about 30 fold of TL1A
compared to the
corresponding tissue in the control subject before the maintenance regimen. In
one specific
embodiment, the diseased tissue in the subject produces up to or about 40 fold
of TL1A
compared to the corresponding tissue in the control subject before the
maintenance regimen.
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In one specific embodiment, the diseased tissue in the subject produces up to
or about 50 fold
of TL1A compared to the corresponding tissue in the control subject before the
maintenance
regimen. In another specific embodiment, the diseased tissue in the subject
produces up to or
about 60 fold of TL1A compared to the corresponding tissue in the control
subject before the
maintenance regimen. In one specific embodiment, the diseased tissue in the
subject
produces up to or about 70 fold of TL1A compared to the corresponding tissue
in the control
subject before the maintenance regimen. In another specific embodiment, the
diseased tissue
in the subject produces up to or about 80 fold of TL1A compared to the
corresponding tissue
in the control subject before the maintenance regimen. In one specific
embodiment, the
diseased tissue in the subject produces up to or about 90 fold of TL1A
compared to the
corresponding tissue in the control subject before the maintenance regimen. In
another
specific embodiment, the diseased tissue in the subject produces up to or
about 100 fold of
TL1A compared to the corresponding tissue in the control subject before the
maintenance
regimen. In one specific embodiment, the diseased tissue in the subject
produces up to or
about 110 fold of TL1A compared to the corresponding tissue in the control
subject before
the maintenance regimen. In another specific embodiment, the diseased tissue
in the subject
produces up to or about 120 fold of TL1A compared to the corresponding tissue
in the control
subject before the maintenance regimen. As is clear from the description
above, by providing
the reductions of TL1A in the diseased tissue in this paragraph with the
methods, the
disclosure also provides that the method provided herein can cover the IL over-
production, for the fold overproduction, timing and/or duration, with the
effective dose or
maintenance regimen, as described in this paragraph.
1003251 Alternatively, in some embodiments of the methods provided herein,
including in
this Section (Section 4.6), the diseased tissue in the subject produces up to
10, up to 15, up to
20, up to 25, up to 30, up to 35, up to 40, up to 45, up to 50, up to 55, up
to 60, up to 65, up to
70, up to 75, up to 80, up to 85, up to 90, up to 95, up to 100, or up to more
fold of TL1A
compared to the corresponding tissue in the control subject within 1, 2, 3, 4,
5, 6, 7, 8, 9, 10,
11, 12, 14, 16, 18, 20, 22, 24,28, 32, 36, 40, 44, 48, or 52 weeks of the
start of the
maintenance regimen. In certain embodiments, the diseased tissue in the
subject produces
about 10, about 15, about 20, about 25, about 30, ab out 35, about 40, about
45, about 50,
about 55, about 60, about 65, about 70, about 75, about 80, about 85, about
90, about 95,
about 100, or about more fold of TL1A compared to the corresponding tissue in
the control
subject within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22, 24,
28, 32, 36, 40, 44, 48,
or 52 weeks of the start of the maintenance regimen. In some embodiments, the
diseased
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tissue in the subject produces 10 to 15,10 to 20, 10 to 25, 10 to 30,10 to 35,
10 to 40, 10 to
45, 10 to 50, 10 to 50, 10 to 55, 10 to 60, 10 to 65, 10 to 70, 10 to 75,10 to
80, 10 to 85, 10 to
90, 10 to 95, 10 to 100 fold of TL1A compared to the corresponding tissue in
the control
subject within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22, 24,
28, 32, 36, 40, 44, 48,
or 52 weeks of the start of the maintenance regimen. In some embodiments, the
diseased
tissue in the subject produces 20 to 25,20 to 30, 20 to 35, 20 to 40,20 to 45,
20 to 50, 20 to
50, 20 to 55, 20 to 60, 20 to 65, 20 to 70, 20 to 75, 20 to 80, 20 to 85,20 to
90, 20 to 95,20 to
100 fold of TL compared to the corresponding tissue in the control
subject within 1, 2, 3,
4, 5, 6,7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22, 24, 28,32, 36,40, 44,48, or
52 weeks of the
start of the maintenance regimen. In some embodiments, the diseased tissue in
the subject
produces 30 to 35,30 to 40,30 to 45,30 to 50,30 to 50,30 to 55,30 to 60,30 to
65,30 to 70,
30 to 75, 30 to 80, 30 to 85, 30 to 90, 30 to 95, 30 to 100 fold of TL1A
compared to the
corresponding tissue in the control subject within 1,2, 3,4, 5, 6, 7, 8,9, 10,
11, 12, 14, 16,
18, 20, 22, 24, 28, 32,36, 40,44, 48, or 52 weeks of the start of the
maintenance regimen. In
some embodiments, the diseased tissue in the subject produces 40 to 45, 40 to
50, 40 to 50,
40 to 55, 40 to 60, 40 to 65, 40 to 70, 40 to 75, 40 to 80, 40 to 85, 40 to
90, 40 to 95,40 to
100 fold of TL1A compared to the corresponding tissue in the control subject
within 1, 2, 3,
4, 5, 6,7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22, 24, 28,32, 36,40, 44,48, or
52 weeks of the
start of the maintenance regimen. In some embodiments, the diseased tissue in
the subject
produces 50 to 55, 50 to 60,50 to 65, 50 to 70, 50 to 75,50 to 80, 50 to 85,
50 to 90,50 to 95,
50 to 100 fold of TL1A compared to the corresponding tissue in the control
subject within 1,
2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18,20, 22,24, 28,32, 36,40,44,48,
or 52 weeks of
the start of the maintenance regimen. In one embodiment, the diseased tissue
in the subject
produces up to or about 10 fold of TL1A compared to the corresponding ti ssue
in the control
subject within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22, 24,
28, 32, 36, 40, 44,48,
or 52 weeks of the start of the maintenance regimen. In one embodiment, the
diseased tissue
in the subject produces up to or about 20 fold of TL1A compared to the
corresponding tissue
in the control subject within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16,
18,20, 22,24, 28,32,
36, 40, 44, 48, or 52 weeks of the start of the maintenance regimen. In one
embodiment, the
diseased tissue in the subject produces up to or about 30 fold of TL1A
compared to the
corresponding tissue in the control subject within 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, 12, 14, 16,
18, 20, 22, 24, 28, 32,36, 40,44, 48, or 52 weeks of the start of the
maintenance regimen. In
one specific embodiment, the diseased tissue in the subject produces up to or
about 40 fold of
TL1A compared to the corresponding tissue in the control subject within 1, 2,
3, 4, 5, 6, 7, 8,
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9, 10, 11, 12, 14, 16, 18, 20, 22, 24, 28, 32, 36, 40, 44, 48, or 52 weeks of
the start of the
maintenance regimen. In one specific embodiment, the diseased tissue in the
subject
produces up to or about 50 fold of TL1A compared to the corresponding tissue
in the control
subject within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22, 24,
28, 32, 36, 40, 44, 48,
or 52 weeks of the start of the maintenance regimen. In another specific
embodiment, the
diseased tissue in the subject produces up to or about 60 fold of TL1A
compared to the
corresponding tissue in the control subject within 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, 12, 14, 16,
18, 20, 22, 24, 28, 32,36, 40,44, 48, or 52 weeks of the start of the
maintenance regimen. In
one specific embodiment, the diseased tissue in the subject produces up to or
about 70 fold of
TL1A compared to the corresponding tissue in the control subject within 1, 2,
3, 4, 5, 6, 7, 8,
9, 10, 11, 12, 14, 16, 18, 20, 22, 24, 28, 32, 36, 40, 44, 48, or 52 weeks of
the start of the
maintenance regimen. In another specific embodiment, the diseased tissue in
the subject
produces up to or about 80 fold of TL1A compared to the corresponding tissue
in the control
subject within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22, 24,
28, 32, 36, 40, 44,48,
or 52 weeks of the start of the maintenance regimen. In one specific
embodiment, the
diseased tissue in the subject produces up to or about 90 fold of TL1A
compared to the
corresponding tissue in the control subject within 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, 12, 14, 16,
18, 20, 22, 24, 28, 32,36, 40, 44, 48, or 52 weeks of the start of the
maintenance regimen. In
another specific embodiment, the diseased tissue in the subject produces up to
or about 100
fold of TL1A compared to the corresponding tissue in the control subject
within 1, 2, 3, 4, 5,
6, 7, 8,9, 10, 11, 12, 14, 16, 18, 20, 22, 24, 28,32, 36, 40, 44,48, or 52
weeks of the start of
the maintenance regimen. In one specific embodiment, the diseased tissue in
the subject
produces up to or about 110 fold of TL1A compared to the corresponding tissue
in the control
subject within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22, 24,
28, 32, 36, 40, 44,48,
or 52 weeks of the start of the maintenance regimen. In another specific
embodiment, the
diseased tissue in the subject produces up to or about 120 fold of TL1A
compared to the
corresponding tissue in the control subject within 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, 12, 14, 16,
18, 20, 22, 24, 28, 32,36, 40,44, 48, or 52 weeks of the start of the
maintenance regimen. As
is clear from the description above, by providing the reductions of TL1A in
the diseased
tissue in this paragraph with the methods, the disclosure also provides that
the method
provided herein can cover the TL1A over-production, for the fold
overproduction, timing
and/or duration, with the effective dose or maintenance regimen, as described
in this
paragraph.
[00326] The disclosure provides that the maintenance regimen can include
multiple
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administrations of the anti-TL1A antibody or antigen binding fragment. In one
embodiment
of the methods provided herein, including in this Section (Section 4.6), the
maintenance
regimen comprises 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18,
19, 20, or more
administrations the anti-TL1A antibody or antigen binding fragments. In
another
embodiment, the maintenance regimen comprises administration of about 2000,
1950, 1900,
1850, 1800, 1750, 1700,1650, 1600, 1550, 1500, 1450, 1400,1350, 1300,1250,
1200,1150,
1100, 1050, 1000, 950, 900, 850, 800, 750, 700, 650, 600, 550, 500, 450, 400,
350, 300, 250,
200, 150, 100, or 50 mg/dose. In one embodiment, the maintenance regimen
comprises
administration of about 50 to 1000, 50 to 950, 50 to 900, 50 to 850, 50 to
800,50 to 750, 50
to 700, 50 to 650, 50 to 600, 50 to 550, 50 to 500,50 to 450, 50 to 400, 50to
350, 50 to 300,
50 to 250, 50 to 200, 50 to 150, or 50 to 100 mg/dose. In another embodiment,
the
maintenance regimen comprises administration of about 100 to 1000, 100 to 950,
100 to 900,
100 to 850, 100 to 800, 100 to 750, 100 to 700, 100 to 650, 100 to 600, 100 to
550, 100 to
500, 100 to 450, 100 to 400, 100 to 350,100 to 300, 100 to 250, 100 to 200, or
100 to 150
mg/dose. In yet another embodiment, the maintenance regimen comprises
administration of
about 200 to 1000,200 to 950, 200to 900, 200 to 850,200 to 800, 200to 750,
200to 700,
200 to 650, 200 to 600, 200 to 550,200 to 500, 200 to 450, 200 to 400,200 to
350, 200 to
300, or 200 to 250 mg/dose. In yet another embodiment, the maintenance regimen
comprises
administration once every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks. In a
further
embodiment, the maintenance regimen continues for 4, 6, 8, 10, 12, 14, 16, 18,
20, 22, 24, 26,
28, 30, 32, 34, 36, 40,44, 48, 52, or more weeks. The disclosure further
provides that the
maintenance regimen can comprise any combination of the dosing amount, dosing
frequency,
number of administrations, and/or the duration of the induction regimen.
Accordingly and as
an example, in some embodiments, the induction regimen can comprise
administration of
about 1000, 950, 900, 850, 800, 750, 700, 650, 600, 550, 500, 450, 400, 350,
300, 250, 200,
150, 100, or 50 mg/dose for administrations at a frequency of once every 1, 2,
3, 4, 5, 6, 7, 8,
9, 10, 11, or 12 weeks, for a duration of 4, 6, 8, 10, 12, 14, 16, 18,20,
22,24, 26,28, 30,32,
34, 36, 40, 44, 48, 52, or more weeks for the maintenance regimen.
1003271
Specifically, in some embodiments of the methods provided herein, including
in
this Section (Section 4.6), the maintenance regimen comprises administrations
of the anti-
TL1A antibody or antigen binding fragment at about 500 mg/dose every 2 weeks.
In one
embodiment, the maintenance regimen comprises administrations of the anti-TL1A
antibody
or antigen binding fragment at about 450 mg/dose every 2 weeks. In one
embodiment, the
maintenance regimen comprises administrations of the anti-TL1A antibody or
antigen
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binding fragment at about 400 mg/dose every 2 weeks. In one embodiment, the
maintenance
regimen comprises administrations of the anti-TLIA antibody or antigen binding
fragment at
about 350 mg/dose every 2 weeks. In one embodiment, the maintenance regimen
comprises
administrations of the anti-TLIA antibody or antigen binding fragment at about
300 mg/dose
every 2 weeks. In one embodiment, the maintenance regimen comprises
administrations of
the anti-TL1A antibody or antigen binding fragment at about 250 mg/dose every
2 weeks. In
one embodiment, the maintenance regimen comprises administrations of the anti-
TL1A
antibody or antigen binding fragment at about 200 mg/dose every 2 weeks. In
one
embodiment, the maintenance regimen comprises administrations of the anti-TL1A
antibody
or antigen binding fragment at about 150 mg/dose every 2 weeks. In one
embodiment, the
maintenance regimen comprises administrations of the anti-TLIA antibody or
antigen
binding fragment at about 100 mg/dose every 2 weeks. In one embodiment, the
maintenance
regimen comprises administrations of the anti-TLIA antibody or antigen binding
fragment at
about 50 mg/dose every 2 weeks. In one embodiment, the maintenance regimen
comprises
administrations of the anti-TLIA antibody or antigen binding fragment at about
500 mg/dose
every 4 weeks. In one embodiment, the maintenance regimen comprises
administrations of
the anti-TLIA antibody or antigen binding fragment at about 450 mg/dose every
4 weeks. In
one embodiment, the maintenance regimen comprises administrations of the anti -
TLIA
antibody or antigen binding fragment at about 400 mg/dose every 4 weeks. In
one
embodiment, the maintenance regimen comprises administrations of the anti-TL1A
antibody
or antigen binding fragment at about 350 mg/dose every 4 weeks. In one
embodiment, the
maintenance regimen comprises administrations of the anti-TL1A antibody or
antigen
binding fragment at about 300 mg/dose every 4 weeks. In one embodiment, the
maintenance
regimen comprises administrations of the anti -TL1A antibody or antigen
binding fragment at
about 250 mg/dose every 4 weeks. In one embodiment, the maintenance regimen
comprises
administrations of the anti-TLIA antibody or antigen binding fragment at about
200 mg/dose
every 4 weeks. In one embodiment, the maintenance regimen comprises
administrations of
the anti-TL 1A antibody or antigen binding fragment at about 150 mg/dose every
4 weeks. In
one embodiment, the maintenance regimen comprises administrations of the anti -
TLIA
antibody or antigen binding fragment at about 100 mg/dose every 4 weeks. In
one
embodiment, the maintenance regimen comprises administrations of the anti-TL1A
antibody
or antigen binding fragment at about 50 mg/dose every 4 weeks. In one
embodiment, the
maintenance regimen comprises administrations of the anti-TL1A antibody or
antigen
binding fragment at about 500 mg/dose every 6 weeks. In one embodiment, the
maintenance
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regimen comprises administrations of the anti-TL1A antibody or antigen binding
fragment at
about 450 mg/dose every 6 weeks. In one embodiment, the maintenance regimen
comprises
administrations of the anti-TL1A antibody or antigen binding fragment at about
400 mg/dose
every 6 weeks. In one embodiment, the maintenance regimen comprises
administrations of
the anti-TL1A antibody or antigen binding fragment at about 350 mg/dose every
6 weeks. In
one embodiment, the maintenance regimen comprises administrations of the anti -
TL1A
antibody or antigen binding fragment at about 300 mg/dose every 6 weeks. In
one
embodiment, the maintenance regimen comprises administrations of the anti-TL1A
antibody
or antigen binding fragment at about 250 mg/dose every 6 weeks. In one
embodiment, the
maintenance regimen comprises administrations of the anti-TL1A antibody or
antigen
binding fragment at about 200 mg/dose every 6 weeks. In one embodiment, the
maintenance
regimen comprises administrations of the anti-TL1A antibody or antigen binding
fragment at
about 150 mg/dose every 6 weeks. In one embodiment, the maintenance regimen
comprises
administrations of the anti-TL1A antibody or antigen binding fragment at about
100 mg/dose
every 6 weeks. In one embodiment, the maintenance regimen comprises
administrations of
the anti-TL1A antibody or antigen binding fragment at about 50 mg/dose every 6
weeks. In
one embodiment, the maintenance regimen comprises administrations of the anti-
TL1A
antibody or antigen binding fragment at about 500 mg/dose every 8 weeks. In
one
embodiment, the maintenance regimen comprises administrations of the anti-TL1A
antibody
or antigen binding fragment at about 450 mg/dose every 8 weeks. In one
embodiment, the
maintenance regimen comprises administrations of the anti-TL1A antibody or
antigen
binding fragment at about 400 mg/dose every 8 weeks. In one embodiment, the
maintenance
regimen comprises administrations of the anti-TL1A antibody or antigen binding
fragment at
about 350 mg/dose every 8 weeks. In one embodiment, the maintenance regimen
comprises
administrations of the anti-TL1A antibody or antigen binding fragment at about
300 mg/dose
every 8 weeks. In one embodiment, the maintenance regimen comprises
administrations of
the anti-TL1A antibody or antigen binding fragment at about 250 mg/dose every
8 weeks. In
one embodiment, the maintenance regimen comprises administrations of the anti -
TL 1 A
antibody or antigen binding fragment at about 200 mg/dose every 8 weeks. In
one
embodiment, the maintenance regimen comprises administrations of the anti-TL1A
antibody
or antigen binding fragment at about 150 mg/dose every 8 weeks. In one
embodiment, the
maintenance regimen comprises administrations of the anti-TL1A antibody or
antigen
binding fragment at about 100 mg/dose every 8 weeks. In one embodiment, the
maintenance
regimen comprises administrations of the anti-TL1A antibody or antigen binding
fragment at
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about 50 mg/dose every 8 weeks. In one embodiment, the maintenance regimen
comprises
administrations of the anti-TL1A antibody or antigen binding fragment at about
500 mg/dose
every 10 weeks. In one embodiment, the maintenance regimen comprises
administrations of
the anti-TL1A antibody or antigen binding fragment at about 450 mg/dose every
10 weeks.
In one embodiment, the maintenance regimen comprises administrations of the
anti-TL1A
antibody or antigen binding fragment at about 400 mg/dose every 10 weeks. In
one
embodiment, the maintenance regimen comprises administrations of the anti-TL1A
antibody
or antigen binding fragment at about 350 mg/dose every 10 weeks. In one
embodiment, the
maintenance regimen comprises administrations of the anti-TL1A antibody or
antigen
binding fragment at about 300 mg/dose every 10 weeks. In one embodiment, the
maintenance regimen comprises administrations of the anti-TL1A antibody or
antigen
binding fragment at about 250 mg/dose every 10 weeks. In one embodiment, the
maintenance regimen comprises administrations of the anti-TL1A antibody or
antigen
binding fragment at about 200 mg/dose every 10 weeks. In one embodiment, the
maintenance regimen comprises administrations of the anti-TL1A antibody or
antigen
binding fragment at about 150 mg/dose every 10 weeks. In one embodiment, the
maintenance regimen comprises administrations of the anti-TL1A antibody or
antigen
binding fragment at about 100 mg/dose every 10 weeks. In one embodiment, the
maintenance regimen comprises administrations of the anti-TL1A antibody or
antigen
binding fragment at about 50 mg/dose every 10 weeks.
1003281 For various embodiments of the methods provided herein, including in
this
Section (Section 4.6, for example those of the preceding paragraphs), further
embodiments of
the anti-TL1A antibodies, including embodiments with exemplary CDRs, framework
sequences, constant region sequences, Fc mutations, variable regions, Fc
regions, and other
properties are further provided in Section 4.2; assays for screening, testing,
and validating the
anti-TL1A antibodies are provided in Section 4.3; methods for generating,
improving,
mutating, cloning, expressing, and isolating the anti-TL1A antibodies are
provided in Section
4.4; pharmaceutical compositions for the anti-TL1A antibodies are described
and provided in
Section 4.5; further specific and validated embodiments for the anti-TL1A
antibodies and the
methods of using the same are provided in Section 5. As such, the disclosure
provides the
various combinations of the anti-TL1A antibodies, the pharmaceutical
compositions of such
anti-TL1A antibodies, the methods of generating the anti-TL1A antibodies, the
methods of
assaying the anti-TL1A antibodies, and the methods of using the anti-TL1A
antibodies for
treatment.
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1003291 The disclosure provides that there is advantage of using anti-TL1A
antibody or
antigen binding fragments that bind to both monomeric TL1A and trimeric TL1A,
as
neutralizing both monomeric and trimeric TL1A can more efficiently reduce the
functional
trimeric TL1A in diseased tissue. For various embodiments of the methods
provided herein,
including in this Section (Section 4.6, for example those of the preceding
paragraphs), the
antibody or antigen binding fragment binds to both monomeric TL1A and trimeric
TL1A. In
some embodiments of the methods provided herein, the anti-TL1A antibody or
antigen
binding fragment blocks binding of TL to DR3. In certain emb odiments of the
methods
provided herein, the anti-TL1A antibody or antigen binding fragment binds to
both
monomeric TL1A and trimeric TL1A and blocks binding of TL1A to DR3.
1003301 The disclosure also provides that the anti-TL1A antibody or antigen
fragments
may neutralize TL1A at various percentage levels for the methods provided
herein, including
in this Section (Section 4.6). In some embodiments of the methods provided
herein, at least
or about 60%, 65%, 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%,
94%, 95%, 96%, 97%, 98%, or 99% of the monomeric TL1A in the blood of the
subject is
neutralized (e.g. occupied and blocked for binding with DR3) by the anti -TL1A
antibody or
antigen binding fragment. In certain embodiments of the methods provided
herein, at least or
about 60%, 65%, 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%,
94%,
95%, 96%, 97%, 98%, or 99% of the trimeric TL1A in the blood of the subject is
neutralized
(e.g. occupied and blocked for binding with DR3) by the anti-TL1A antibody or
antigen
binding fragment. In some further embodiments of the methods provided herein,
(i) at least
or about 60%, 65%, 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%,
94%, 95%, 96%, 97%, 98%, or 99% of the monomeric TL1A and (ii) at least or
about 60%,
65%, 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%,
96%,
97%, 98%, or 99% of the trimeric TL1A in the blood of the subject are
neutralized (e.g.
occupied and blocked for binding with DR3) by the anti-TL1A antibody or
antigen binding
fragment. In certain embodiments of the methods provided herein, at least or
about 90% of
the monomeric TL1A in the blood of the subject is neutralized (e.g. occupied
and blocked for
binding with DR3) by the anti-TL1A antibody or antigen binding fragment. In
certain
embodiments of the methods provided herein, at least or about 90% of the
trimeric TL1A in
the blood of the subject is neutralized (e.g. occupied and blocked for binding
with DR3) by
the anti-TL1A antibody or antigen binding fragment. In some further
embodiments of the
methods provided herein, (i) at least or about 90% of the monomeric TL1A and
(ii) at least or
about 90% of the trimeric TL1A in the blood of the subject are neutralized
(e.g. occupied and
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blocked for binding with DR3) by the anti-TL1A antibody or antigen binding
fragment. In
certain embodiments of the methods provided herein, at least or about 95% of
the monomeric
TL1A in the blood of the subject is neutralized (e.g occupied and blocked for
binding with
DR3) by the anti-TL1A antibody or antigen binding fragment. In certain
embodiments of the
methods provided herein, at least or about 95% of the trimeric TL1A in the
blood of the
subject is neutralized (e.g. occupied and blocked for binding with DR3) by the
anti-TL1A
antibody or antigen binding fragment. In some further embodiments of the
methods provided
herein, (i) at least or about 95% of the monomeric TL1A and (ii) at least or
about 95% of the
trimeric TL1A in the blood of the subject are neutralized (e.g. occupied and
blocked for
binding with DR3) by the anti-TL1A antibody or antigen binding fragment. In
certain
embodiments of the methods provided herein, at least or about 99% of the
monomeric TL1A
in the blood of the subject is neutralized (e.g. occupied and blocked for
binding with DR3) by
the anti-TL1A antibody or antigen binding fragment. In certain embodiments of
the methods
provided herein, at least or about 99% of the trimeric TL1A in the blood of
the subject is
neutralized (e.g. occupied and blocked for binding with DR3) by the anti-TL1A
antibody or
antigen binding fragment. In some further embodiments of the methods provided
herein, (i)
at least or about 99% of the monomeric TL1A and (ii) at least or about 99% of
the trimeric
MIA in the blood of the subject are neutralized (e.g. occupied and blocked for
binding with
DR3) by the anti-TL1A antibody or antigen binding fragment.
[00331] The diseased tissue described or referenced in the various methods
provided
herein, including in this Section (Section 4.6), can be one or more tissues
manifesting
pathology from IBD in the subject. In one embodiment, the diseased tissues
comprise or
consist of colon. In some embodiments, the diseased tissues comprise or
consist of small
intestine. In certain embodiments, the diseased tissues comprise or consist of
rectum. In
other embodiments, the diseased tissues comprise or consist of cecum. In yet
other
embodiments, the diseased tissues comprise or consist of ileum. In another
embodiment, the
diseased tissues comprise or consist of a fibrotic tissue from IBD. In yet
another
embodiment, the diseased tissues comprise or consist of other tissues with IBD
pathology. In
yet another embodiment, the diseased tissues comprise or consist of spleen. In
some
embodiments, the diseased tissues comprise or consist of other tissues of IBD
pathogenesis.
In one embodiment, the diseased tissues comprise or consist of colon and small
intestine. In
some embodiments, the diseased tissues comprise or consist of colon and
rectum. In certain
embodiments, the diseased tissues comprise or consist of colon and cecum. In
other
embodiments, the diseased tissues comprise or consist of colon and ileum. In
some
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embodiments, the diseased tissues comprise or consist of colon and a fibrotic
tissue from
IBD. In other embodiments, the diseased tissues comprise or consist of colon
and other
tissues with IBD pathology (or of IBD pathogenesis). In further embodiments,
the diseased
tissues comprise or consist of small intestine and rectum. In one embodiment,
the diseased
tissues comprise or consist of small intestine and cecum. In some embodiments,
the diseased
tissues comprise or consist of small intestine and ileum. In certain
embodiments, the diseased
tissues comprise or consist of small intestine and a fibrotic tissue from IBD.
In some
embodiments, the diseased tissues comprise or consist of small intestine and
other tissues
with IBD pathology (or of IBD pathogenesis). In other embodiments, the
diseased tissues
comprise or consist of rectum and cecum. In yet other embodiments, the
diseased tissues
comprise or consist of rectum and ileum. In some embodiments, the diseased
tissues
comprise or consist of rectum and a fibrotic tissue from IBD. In certain
embodiments, the
diseased tissues comprise or consist of rectum and other tissues with IBD
pathology (or of
IBD pathogenesis). In one embodiment, the diseased tissues comprise or consist
of cecum
and ileum. In another embodiment, the diseased tissues comprise or consist of
cecum and a
fibrotic tissue from IBD. In one embodiment, the diseased tissues comprise or
consist of
cecum and other tissues with IBD pathology (or of IBD pathogenesis). In some
embodiments, the diseased tissues comprise or consist of ileum and a fibrotic
tissue from
IBD. In certain embodiments, the diseased tissues comprise or consist of ileum
and other
tissues with IBD pathology (or of IBD pathogenesis). In one embodiment, the
diseased
tissues comprise or consist of a fibrotic tissue from IBD and other tissues
with IBD pathology
(or of IBD pathogenesis). In other embodiments, the diseased tissues comprise
or consist of
colon, small intestine, and rectum. In yet other embodiments, the diseased
tissues comprise
or consist of colon, small intestine and cecum. In further embodiments, the
diseased tissues
comprise or consist of colon, small intestine, and ileum. In some embodiments,
the diseased
tissues comprise or consist of colon, small intestine, and a fibrotic tissue
from IBD. In
certain embodiments, the diseased tissues comprise or consist of colon, small
intestine, and
other tissues with IBD pathology (or of IBD pathogenesis). In some
embodiments, the
diseased tissues comprise or consist of colon, rectum and cecum. In certain
emb odiments,
the diseased tissues comprise or consist of colon, rectum, and ileum. In some
embodiments,
the diseased tissues comprise or consist of colon, rectum, and a fibrotic
tissue from IBD. In
other embodiments, the diseased tissues comprise or consist of colon, rectum,
and other
tissues with IBD pathology (or of IBD pathogenesis). In yet other embodiments,
the diseased
tissues comprise or consist of colon, cecum and ileum. In some embodiments,
the diseased
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tissues comprise or consist of colon, cecum and a fibrotic tissue from IBD. In
other
embodiments, the diseased tissues comprise or consist of colon, cecum and
other tissues with
IBD pathology (or of IBD pathogenesis). In some embodiments, the diseased
tissues
comprise or consist of colon, ileum and a fibrotic tissue from MD. In certain
embodiments,
the diseased tissues comprise or consist of colon, ileum and other tissues
with IBD pathology
(or of IBD pathogenesis). In other embodiments, the diseased tissues comprise
or consist of
colon, a fibrotic tissue from IBD and other tissues with IBD pathology (or of
IBD
pathogenesis). In some embodiments, the diseased tissues comprise or consist
of small
intestine, rectum and cecum. In certain embodiments, the diseased tissues
comprise or
consist of small intestine, rectum, and ileum. In some embodiments, the
diseased tissues
comprise or consist of small intestine, rectum, and a fibrotic tissue from
IBD. In certain
embodiments, the diseased tissues comprise or consist of small intestine,
rectum, and other
tissues with IBD pathology (or of IBD pathogenesis). In other embodiments, the
diseased
tissues comprise or consist of small intestine, cecum and ileum. In yet other
embodiments,
the diseased tissues comprise or consist of small intestine, cecum and a
fibrotic tissue from
IBD. In some embodiments, the diseased tissues comprise or consist of small
intestine,
cecum and other tissues with IBD pathology (or of IBD pathogenesis). In some
embodiments, the diseased tissues comprise or consist of small intestine,
ileum and a fibrotic
tissue from IBD. In some embodiments, the diseased tissues comprise or consist
of small
intestine, ileum and other tissues with IBD pathology (or of IBD
pathogenesis). In some
embodiments, the diseased tissues comprise or consist of small intestine, a
fibrotic tissue
from IBD and other tissues with IBD pathology (or of 'BD pathogenesis). In yet
other
embodiments, the diseased tissues comprise or consist of rectum, cecum and
ileum. In other
embodiments, the diseased tissues comprise or consist of rectum, cecum and a
fibrotic tissue
from IBD. In some embodiments, the diseased tissues comprise or consist of
rectum, cecum
and other tissues with IBD pathology (or of IBD pathogenesis). In certain
embodiments, the
diseased tissues comprise or consist of rectum, ileum and a fibrotic tissue
from IBD. In other
embodiments, the diseased tissues comprise or consist of rectum, ileum and
other tissues with
MD pathology (or of IBD pathogenesis). In yet other embodiments, the diseased
tissues
comprise or consist of rectum, a fibrotic tissue from IBD and other tissues
with IBD
pathology (or of IBD pathogenesis). In some embodiments, the diseased tissues
comprise or
consist of cecum, ileum and a fibrotic tissue from IBD. In some embodiments,
the diseased
tissues comprise or consist of cecum, ileum and other tissues with IBD
pathology (or of IBD
pathogenesis). In some embodiments, the diseased tissues comprise or consist
of cecum, a
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fibrotic tissue from IBD and other tissues with IBD pathology (or of IBD
pathogenesis). In
some embodiments, the diseased tissues comprise or consist of ileum, a
fibrotic tissue from
IBD and other tissues with IBD pathology (or of IBD pathogenesis). In other
embodiments,
the diseased tissues comprise or consist of colon, small intestine, rectum,
and cecum. In
further embodiments, the diseased tissues comprise or consist of colon, small
intestine,
rectum, and ileum. In some embodiments, the diseased tissues comprise or
consist of colon,
small intestine, rectum, and a fibrotic tissue from IBD. In other embodiments,
the diseased
tissues comprise or consist of colon, small intestine, rectum, and other
tissues with IBD
pathology (or of IBD pathogenesis). In some embodiments, the diseased tissues
comprise or
consist of colon, small intestine, cecum, and ileum. In some embodiments, the
diseased
tissues comprise or consist of colon, small intestine, cecum, and a fibrotic
tissue from IBD.
In some embodiments, the diseased tissues comprise or consist of colon, small
intestine,
cecum, and other tissues with IBD pathology (or of IBD pathogenesis). In some
embodiments, the diseased tissues comprise or consist of colon, small
intestine, ileum, and a
fibrotic tissue from IBD. In some embodiments, the diseased tissues comprise
or consist of
colon, small intestine, ileum, and other tissues with IBD pathology (or of IBD
pathogenesis).
In some embodiments, the diseased tissues comprise or consist of colon, small
intestine, a
fibrotic tissue from IBD, and other tissues with IBD pathology (or of IBD
pathogenesis). In
certain embodiments, the diseased tissues comprise or consist of colon,
rectum, cecum, and
ileum. In certain embodiments, the diseased tissues comprise or consist of
colon, rectum,
cecum, and a fibrotic tissue from IBD. In some embodiments, the diseased
tissues comprise
or consist of colon, rectum, cecum, and other tissues with IBD pathology (or
of IBD
pathogenesis). In certain embodiments, the diseased tissues comprise or
consist of colon,
rectum, ileum, and a fibrotic tissue from IBD. In some embodiments, the
diseased tissues
comprise or consist of colon, rectum, ileum, and othertissues with IBD
pathology (or of IBD
pathogenesis). In other embodiments, the diseased tissues comprise or consist
of colon,
rectum, a fibrotic tissue from IBD, and other tissues with IBD pathology (or
of IBD
pathogenesis). In yet other embodiments, the diseased tissues comprise or
consist of colon,
cecum, ileum, and a fibrotic tissue from IBD. In some embodiments, the
diseased tissues
comprise or consist of colon, cecum, ileum, and other tissues with IBD
pathology (or of IBD
pathogenesis). In certain embodiments, the diseased tissues comprise or
consist of colon,
cecum, a fibrotic tissue from IBD, and other tissues with IBD pathology (or of
IBD
pathogenesis). In other embodiments, the diseased tissues comprise or consist
of colon,
ileum, a fibrotic tissue from IBD, and other tissues with IBD pathology (or of
IBD
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pathogenesis). In further embodiments, the diseased tissues comprise or
consist of small
intestine, rectum, cecum, and ileum. In some embodiments, the diseased tissues
comprise or
consist of small intestine, rectum, cecum, and a fibrotic tissue from IBD. In
certain
embodiments, the diseased tissues comprise or consist of small intestine,
rectum, cecum, and
other tissues with MD pathology (or of IBD pathogenesis). In further
embodiments, the
diseased tissues comprise or consist of small intestine, rectum, ileum, and a
fibrotic tissue
from MD. In other embodiments, the diseased tissues comprise or consist of
small intestine,
rectum, ileum, and other tissues with MD pathology (or of IBD pathogenesis).
In some
embodiments, the diseased tissues comprise or consist of small intestine,
rectum, a fibrotic
tissue from IBD, and other tissues with IBD pathology (or of IBD
pathogenesis). In some
embodiments, the diseased tissues comprise or consist of small intestine,
cecum, ileum, and a
fibrotic tissue from IBD. In some embodiments, the diseased tissues comprise
or consist of
small intestine, cecum, ileum, and other tissues with 1BD pathology (or of IBD
pathogenesis).
In some embodiments, the diseased tissues comprise or consist of small
intestine, cecum, a
fibrotic tissue from IBD, and other tissues with IBD pathology (or of IBD
pathogenesis). In
some embodiments, the diseased tissues comprise or consist of small intestine,
ileum, a
fibrotic tissue from IBD, and other tissues with IBD pathology (or of IBD
pathogenesis). In
some embodiments, the diseased tissues comprise or consist of rectum, cecum,
ileum, and a
fibrotic tissue from IBD. In some embodiments, the diseased tissues comprise
or consist of
rectum, cecum, ileum, and other tissues with MD pathology (or of IBD
pathogenesis). In
some embodiments, the diseased tissues comprise or consist of rectum, cecum, a
fibrotic
tissue from IBD, and other tissues with IBD pathology (or of IBD
pathogenesis). In some
embodiments, the diseased tissues comprise or consist of rectum, ileum, a
fibrotic tissue from
IBD, and other tissues with IBD pathology (or of IBD pathogenesis). In some
embodiments,
the diseased tissues comprise or consist of cecum, ileum, a fibrotic tissue
from IBD, and other
tissues with IBD pathology (or of IBD pathogenesis). In certain embodiments,
the diseased
tissues comprise or consist of colon, small intestine, rectum, cecum, and
ileum. In some
embodiments, the diseased tissues comprise or consist of colon, small
intestine, rectum,
cecum, and a fibrotic tissue from IBD. In certain embodiments, the diseased
tissues comprise
or consist of colon, small intestine, rectum, cecum, and other tissues with
'BD pathology (or
of MD pathogenesis). In some embodiments, the diseased tissues comprise or
consist of
colon, small intestine, rectum, ileum, and a fibrotic tissue from MD. In
certain embodiments,
the diseased tissues comprise or consist of colon, small intestine, rectum,
ileum, and other
tissues with IBD pathology (or of IBD pathogenesis). In some embodiments, the
diseased
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tissues comprise or consist of colon, small intestine, rectum, a fibrotic
tissue from IBD, and
other tissues with IBD pathology (or of IBD pathogenesis). In certain
embodiments, the
diseased tissues comprise or consist of colon, small intestine, cecum, ileum,
and a fibrotic
tissue from IBD. In some embodiments, the diseased tissues comprise or consist
of colon,
small intestine, cecum, ileum, and other tissues with IBD pathology (or of IBD
pathogenesis).
In certain embodiments, the diseased tissues comprise or consist of colon,
small intestine,
cecum, a fibrotic tissue from IBD, and other tissues with IBD pathology (or of
IBD
pathogenesis). In some embodiments, the diseased tissues comprise or consist
of colon, small
intestine, ileum, a fibrotic tissue from IBD, and other tissues with IBD
pathology (or of IBD
pathogenesis). In certain embodiments, the diseased tissues comprise or
consist of colon,
rectum, cecum, ileum, and a fibrotic tissue from IBD. In some embodiments, the
diseased
tissues comprise or consist of colon, rectum, cecum, ileum, and other tissues
with IBD
pathology (or of IBD pathogenesis). In certain embodiments, the diseased
tissues comprise
or consist of colon, rectum, cecum, a fibrotic tissue from IBD, and other
tissues with IBD
pathology (or of IBD pathogenesis). In some embodiments, the diseased tissues
comprise or
consist of colon, rectum, ileum, a fibrotic tissue from IBD, and other tissues
with IBD
pathology (or of IBD pathogenesis). In certain embodiments, the diseased
tissues comprise
or consist of colon, cecum, ileum, a fibrotic tissue from IBD, and other
tissues with IBD
pathology (or of IBD pathogenesis). In some embodiments, the diseased tissues
comprise or
consist of small intestine, rectum, cecum, ileum, and a fibrotic tissue from
IBD. In certain
embodiments, the diseased tissues comprise or consist of small intestine,
rectum, cecum,
ileum, and other tissues with IBD pathology (or of IBD pathogenesis). In some
embodiments, the diseased tissues comprise or consist of small intestine,
rectum, cecum, a
fibrotic tissue from IBD, and other tissues with IBD pathology (or of IBD
pathogenesis). In
some embodiments, the diseased tissues comprise or consist of small intestine,
rectum, ileum,
a fibrotic tissue from IBD, and other tissues with IBD pathology (or of IBD
pathogenesis). In
certain embodiments, the diseased tissues comprise or consist of small
intestine, cecum,
ileum, a fibrotic tissue from IBD, and other tissues with IBD pathology (or of
IBD
pathogenesis). In some embodiments, the diseased tissues comprise or consist
of rectum,
cecum, ileum, a fibrotic tissue from IBD, and other tissues with IBD pathology
(or of IBD
pathogenesis). In some embodiments, the diseased tissues comprise or consist
of colon, small
intestine, rectum, cecum, ileum, and a fibrotic tissue from IBD. In certain
embodiments, the
diseased tissues comprise or consist of colon, small intestine, rectum, cecum,
ileum, and other
tissues with IBD pathology (or of IBD pathogenesis). In some embodiments, the
diseased
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tissues comprise or consist of colon, small intestine, rectum, cecum, a
fibrotic tissue from
IBD, and other tissues with IBD pathology (or of IBD pathogenesis). In certain
embodiments, the diseased tissues comprise or consist of colon, small
intestine, rectum,
ileum, a fibrotic tissue from IBD, and other tissues with IBD pathology (or of
IBD
pathogenesis). In some embodiments, the diseased tissues comprise or consist
of colon, small
intestine, cecum, ileum, a fibrotic tissue from IBD, and other tissues with
IBD pathology (or
of IBD pathogenesis). In certain embodiments, the diseased tissues comprise or
consist of
colon, rectum, cecum, ileum, a fibrotic tissue from IBD, and other tissues
with IBD
pathology (or of IBD pathogenesis). In some embodiments, the diseased tissues
comprise or
consist of small intestine, rectum, cecum, ileum, a fibrotic tissue from IBD,
and other tissues
with IBD pathology (or of IBD pathogenesis). In some embodiments, the diseased
tissues
comprise or consist of any one of colon, small intestine, rectum, cecum,
ileum, a fibrotic
tissue from IBD, and other tissues with IBD pathology (or of IBD
pathogenesis). In some
embodiments, the diseased tissues comprise or consist of any two of colon,
small intestine,
rectum, cecum, ileum, a fibrotic tissue from IBD, and other tissues with IBD
pathology (or of
IBD pathogenesis), in any combination or permutation. In some embodiments, the
diseased
tissues comprise or consist of any three of colon, small intestine, rectum,
cecum, ileum, a
fibrotic tissue from IBD, and other tissues with IBD pathology (or of IBD
pathogenesis), in
any combination or permutation. In some embodiments, the diseased tissues
comprise or
consist of any four of colon, small intestine, rectum, cecum, ileum, a
fibrotic tissue from IBD,
and other tissues with IBD pathology (or of IBD pathogenesis), in any
combination or
permutation. In some embodiments, the diseased tissues comprise or consist of
any five of
colon, small intestine, rectum, cecum, ileum, a fibrotic tissue from IBD, and
other tissues
with IBD pathology (or of IBD pathogenesis), in any combination or
permutation. In some
embodiments, the diseased tissues comprise or consist of any six of colon,
small intestine,
rectum, cecum, ileum, a fibrotic tissue from IBD, and other tissues with IBD
pathology (or of
IBD pathogenesis), in any combination or permutation. In some embodiments, the
diseased
tissues comprise or consist of all seven of colon, small intestine, rectum,
cecum, ileum, a
fibrotic tissue from IBD, and other tissues with IBD pathology (or of IBD
pathogenesis).
1003321 As is clear from the previous paragraph, the diseased tissue can also
include
spleen. In one embodiment, the diseased tissues comprise or consist of spleen
and any one
selected from the group consisting of colon, small intestine, rectum, cecum,
ileum, a fibrotic
tissue from IBD, other tissues with IBD pathology, and other tissues of IBD
pathogenesis. In
one embodiment, the diseased tissues comprise or consist of spleen and any two
selected
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from the group consisting of colon, small intestine, rectum, cecum, ileum, a
fibrotic tissue
from IBD, other tissues with IBD pathology, and other tissues of IBD
pathogenesis. In one
embodiment, the diseased tissues comprise or consist of spleen and any three
selected from
the group consisting of colon, small intestine, rectum, cecum, ileum, a
fibrotic tissue from
IBD, other tissues with IBD pathology, and other tissues of IBD pathogenesis.
In one
embodiment, the diseased tissues comprise or consist of spleen and any four
selected from
the group consisting of colon, small intestine, rectum, cecum, ileum, a
fibrotic tissue from
IBD, other tissues with IBD pathology, and other tissues of IBD pathogenesis.
In one
embodiment, the diseased tissues comprise or consist of spleen and any five
selected from the
group consisting of colon, small intestine, rectum, cecum, ileum, a fibrotic
tissue from IBD,
other tissues with IBD pathology, and other tissues of IBD pathogenesis. In
one
embodiment, the diseased tissues comprise or consist of spleen and any six
selected from the
group consisting of colon, small intestine, rectum, cecum, ileum, a fibrotic
tissue from IBD,
other tissues with IBD pathology, and other tissues of IBD pathogenesis. In
one
embodiment, the diseased tissues comprise or consist of spleen and any seven
selected from
the group consisting of colon, small intestine, rectum, cecum, ileum, a
fibrotic tissue from
IBD, other tissues with IBD pathology, and other tissues of IBD pathogenesis.
In one
embodiment, the diseased tissues comprise or consist of spleen and all eight
selected from the
group consisting of colon, small intestine, rectum, cecum, ileum, a fibrotic
tissue from IBD,
other tissues with IBD pathology, and other tissues of IBD pathogenesis. In
one
embodiment, the diseased tissues comprise or consist of any one selected from
the group
consisting of colon, small intestine, rectum, cecum, ileum, spleen, a fibrotic
tissue from IBD,
other tissues with IBD pathology, and other tissues of IBD pathogenesis. In
one
embodiment, the diseased tissues comprise or consist of any two selected from
the group
consisting of colon, small intestine, rectum, cecum, ileum, spleen, a fibrotic
tissue from IBD,
other tissues with IBD pathology, and other tissues of IBD pathogenesis. In
one
embodiment, the diseased tissues comprise or consist of any three selected
from the group
consisting of colon, small intestine, rectum, cecum, ileum, spleen, a fibrotic
tissue from IBD,
other tissues with IBD pathology, and other tissues of IBD pathogenesis. In
one
embodiment, the diseased tissues comprise or consist of any four selected from
the group
consisting of colon, small intestine, rectum, cecum, ileum, spleen, a fibrotic
tissue from IBD,
other tissues with IBD pathology, and other tissues of lBD pathogenesis. In
one
embodiment, the diseased tissues comprise or consist of any five selected from
the group
consisting of colon, small intestine, rectum, cecum, ileum, spleen, a fibrotic
tissue from IBD,
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other tissues with IBD pathology, and other tissues of IBD pathogenesis. In
one
embodiment, the diseased tissues comprise or consist of any six selected from
the group
consisting of colon, small intestine, rectum, cecum, ileum, spleen, a fibrotic
tissue from IBD,
other tissues with MD pathology, and other tissues of IBD pathogenesis. In one
embodiment, the diseased tissues comprise or consist of any seven selected
from the group
consisting of colon, small intestine, rectum, cecum, ileum, spleen, a fibrotic
tissue from MD,
other tissues with IBD pathology, and other tissues of IBD pathogenesis. In
one
embodiment, the diseased tissues comprise or consist of any eight selected
from the group
consisting of colon, small intestine, rectum, cecum, ileum, spleen, a fibrotic
tissue from IBD,
other tissues with IBD pathology, and other tissues of IBD pathogenesis. In
one
embodiment, the diseased tissues comprise or consist of all nine selected from
the group
consisting of colon, small intestine, rectum, cecum, ileum, spleen, a fibrotic
tissue from IBD,
other tissues with IBD pathology, and other tissues of IBD pathogenesis. For
clarity, in some
embodiments, the diseased tissues comprise or consist of any number of tissues
(e.g. one or
more), in any combination or permutation, selected from the group consisting
of colon, small
intestine, rectum, cecum, ileum, spleen, a fibrotic tissue from IBD, other
tissues with IBD
pathology, and other tissues of IBD pathogenesis.
[00333] The tissues with MD pathology refers to tissues that have manifested
changes
caused by IBD. Such manifested changes for IBD pathology can be changes in
gene or
protein expression profile (e.g. higher TL1A expression and/or IFNy
expression), histology
changes (e.g. changes in the organization and arrangements of the various cell
types (such as
damages to layers of epithelial cells), changes in the amount or ratio of cell
various cells
types (such as loss of certain cells or over-amplification of some cells),
and/or occurrence of
cell types not normally seen in the tissue (such as infiltration of m on
ocytes in the tissue)).
[00334] The tissues of MD pathogenesis refers to tissues that have manifested
changes
that will cause or contribute to the development of IBD. Such manifested
changes of IBD
pathogenesis can be changes in gene or protein expression profile (e.g. higher
TL1A
expression and/or IFNy expression), changes in the transportation of proteins
or cells (e.g.
increased secretion of TL1A and/or IFN7 or increased migration of monocyte to
other tissues
of MD pathology), and/or other changes that can cause inflammation in the
tissues of IBD
pathology. The disclosure provides that the tissues of IBD pathogenesis and
the tissues with
IBD pathology are not mutually exclusive. Thus certain tissues of IBD
pathogenesis can also
be tissues with IBD pathology and some tissues with IBD pathology can also be
tissues of
MD pathogenesis.
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1003351 The corresponding tissue provided herein for the various methods for
determining
the fold overproduction of TL1A in the diseased tissue can be the same or
equivalent tissue as
the diseased tissue but in a control subject without IBD. For example, when
the diseased
tissue in an IBD patient is colon, the corresponding tissue can be colon, or
one or more parts
of colon, tissue close to colon, or tissue whose TL1A level correlates with
that in colon.
Alternatively, the corresponding tissue provided herein for the various
methods for
determining the fold overproduction of TL1A in the diseased tissue can be a
reference tissue
in a control subject without IBD. Additionally, the corresponding tissue
provided herein for
the various methods for determining the fold overproduction of TL1A in the
diseased tissue
can be a reference tissue that is not affected by the IBD in the same diseased
subject. Such
reference tissues are not necessarily the same as the diseased tissue, as long
as the TL1A
concentration in such reference tissue reflects the physiological or basal
level of TL1A
production as further described in the paragraph b elow, Such reference
tissues in a control
subject can be colon, small intestine, rectum, cecum, spleen, ileum, and/or a
tissue (or tissues)
without IBD pathology or abnormal TL1A expression. In one embodiment, the
corresponding tissue or reference tissue in the control subject comprises or
consists of colon.
In one embodiment, the corresponding tissue or reference tissue in the control
subject
comprises or consists of small intestine. In one embodiment, the corresponding
tissue or
reference tissue in the control subject comprises or consists of rectum. In
one embodiment,
the corresponding tissue or reference tissue in the control subject comprises
or consists of
cecum. In one embodiment, the corresponding tissue or reference tissue in the
control subject
comprises or consists of ileum. In one embodiment, the corresponding tissue or
reference
tissue in the control subject comprises or consists of a tissue (or tissues)
without IBD
pathology or abnormal TL1A expression. In one embodiment, the corresponding
tissue or
reference tissue in the control subject comprises or consists of any
combination of 2, 3, 4, 5,
6, or more tissues selected from the group consisting of colon, small
intestine, rectum, cecum,
ileum, spleen, and other tissues without IBD pathology or abnormal TL1A
expression. In
one embodiment, the corresponding tissue or reference tissue in the control
subject comprises
or consists of any combination of 2 tissues selected from the group consisting
of colon, small
intestine, rectum, cecum, ileum, spleen, and a tissue (or tissues) without IBD
pathology or
abnormal TL1A expression. In one embodiment, the corresponding tissue or
reference tissue
in the control subject comprises or consists of any combination of 3 tissues
selected from the
group consisting of colon, small intestine, rectum, cecum, ileum, spleen, and
a tissue (or
tissues) without IBD pathology or abnormal TL1A expression. In one embodiment,
the
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corresponding tissue or reference tissue in the control subject comprises or
consists of any
combination of 4 tissues selected from the group consisting of colon, small
intestine, rectum,
cecum, ileum, spleen, and a tissue (or tissues) without IBD pathology or
abnormal TL1A
expression. In one embodiment, the corresponding tissue or reference tissue in
the control
subject comprises or consists of any combination of 5 tissues selected from
the group
consisting of colon, small intestine, rectum, cecum, ileum, spleen, and a
tissue (or tissues)
without IBD pathology or abnormal TL IA expression. In one embodiment, the
corresponding tissue or reference tissue in the control subject comprises or
consists of any
combination of 6 tissues selected from the group consisting of colon, small
intestine, rectum,
cecum, ileum, spleen, and a tissue (or tissues) without IBD pathology or
abnormal TL1A
expression. In some embodiments of the various methods provided herein,
including in this
Section (Section 4.6), the fold overproduction of TL in the diseased tissue
can be
determined over a reference level of TL1A instead of over the TL1A level in
the
corresponding tissue in a control subject without IBD. Such reference level of
TL1A can be
a specific concentration, a specific unit of TL1A protein, and/or a specific
proxy
measurement of TL1 A.
1003361 As used herein, the TL1A concentration in the corresponding tissue or
the
reference tissue used for comparing with a diseased tissue for the TL1A over-
production
refers to the TL concentration in such corresponding tissue or
reference tissue at the
physiological or basal level of TL1A production under normal healthy
conditions, i.e. without
IBD or other disease or conditions (e.g. inflammatory or immunodeficient
conditions) that
increases or suppresses TL1A production. In other words, the corresponding
tissue or the
reference tissue used herein refer to normal healthy tissues without pathology
or stimuli that
result in abnormal TL1A production. Such physiological or basal level of TL1A
can be the
average of TL
concentrations in the corresponding tissue or the reference tissue during a
time period, if the TL1A concentration fluctuates with the normal healthy
physiological
activity of such tissue during the time period. In some embodiments, the
period of time used
to average the TL1A concentration can be, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
12, 13, 14, 15, 16,
17, 18, 19, 20, 21, 22, 23, or 24 hours, or 1, 2, 3, 4, 5, 6, 7 days. The
reference tissue is also
referred to as the normal reference tissue in some descriptions herein for
clarity.
1003371 As is clear from the descriptions herein, the subject that
is the target for
administering the anti-TL1A antibodies or antigen binding fragments in the
various methods
provided herein can be a subject having IBD. In one embodiment, the subject
that is the
target for administering the anti-TL1A antibodies or antigen binding fragments
in the various
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methods provided herein is a patient with a diseased tissue (e.g. as described
above) from
IBD. In another embodiment, the subject that is the target for administering
the anti-TL1A
antibodies or antigen binding fragments in the various methods provided herein
is a human
subject. In another embodiment, the subject that is the target for
administering the anti-TL1A
antibodies or antigen binding fragments in the various methods provided herein
is an 1113D
patient. In a further embodiment, the subject that is the target for
administering the anti-
TL IA antibodies or antigen binding fragments in the various methods provided
herein is a
patient with ulcerative colitis. In yet another embodiment, the subject that
is the target for
administering the anti-TL1A antibodies or antigen binding fragments in the
various methods
provided herein is a patient with Crohn's disease. In one embodiment, the
subject that is the
target for administering the anti-TL1A antibodies or antigen binding fragments
in the various
methods provided herein is a patient with both ulcerative colitis and Crohn's
disease.
1003381 The disclosure provides that the effective dose provided herein for
the methods,
including in this Section (Section 4.6), can be determined by a dose
determination methods as
further described in this Section (Section 4.6, including the below
paragraphs). Thus in
various aspects and embodiments, provided herein is a method for determining
the effective
dose, including the induction regimen, the maintenance regimen, and both the
induction
regimen and the maintenance regimen.
1003391 In one aspect, provided herein is a method of determining an effective
dose
regimen for administering an anti-TLIA antibody, wherein the method comprises:
(a)
receiving association rate of the antibody to monomeric TL1A (k on-monomer),
association rate
of the antibody to trimeric TL I A (kon_inmõ), dissociation rate of the
antibody from monomeric
TLIA (koir.õ,,,õ0õ,,,), dissociation rate of the antibody from trimeric TLIA
(koir_inme,), synthesis
rate of TL1 A in normal tissue (lc syn_nonna0, synthesis rate of TL1 A in
diseased tissue
disease), degradation rate of monomeric TL1 A (kdeg-menemer), and degradation
rate of trimeric
TL1A (kdeg-iiimet); (b) integrating the rates received in (a) to an integrated
whole-body
physiologically based pharmacokinetic (PBPK) model; and (c) determining the
effective
dose regimen of the anti-TL1 A antibody with the PBPK model from (b) such that
after
administration of the effective dose regimen the concentration of TL1A in a
diseased tissue in
the subject is below the concentration of TL1A in a corresponding tissue in a
control subject
without IBD.
1003401 In another aspect, provided herein is a method of determining an
effective dose
regimen for administering an anti-TL1A antibody, wherein the method comprises:
(a)
receiving association rate of the antibody to monomeric TL I A (k on-monomer),
association rate
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of the antibody to trimeric TL1A (kon-ttimei), dissociation rate of the
antibody from monomeric
TL1A (koff.õ,,,õ,,õ1õ), dissociation rate of the antibody from trimeric TL1A
(koffiii,õ), synthesis
rate of TL1A in normal tissue (ksyn-nomtal), synthesis rate of TL1A in
diseased tissue (ksyn_
disease), degradation rate of monomeric TL1A (kdeg-monomer), and degradation
rate of trimeric
TL1A (kdeg-trimer), integrating the rates received in (a) to a population
pharmacokinetic
(popPK) model; and determining the effective dose regimen of the anti-TL1A
antibody with
the popPK model from (b) such that after administration of the effective dose
regimen the
concentration of TL1A in a diseased tissue in the subject is below the
concentration of TL1A
in a corresponding tissue in a control subject without IBD.
[00341] In a further aspect, provided herein is a method of determining an
effective dose
regimen for administering an anti-TL1A antibody to a diseased subject, wherein
the method
comprises: (a) receiving a parameter of TL1A over-production in the diseased
tissue
comparing to TL1A production in a normal reference tissue; (b) integrating the
parameter
received in (a) to an integrated whole-body physiologically based
pharmacokinetic (PBPK)
model; and (c) determining the effective dose regimen of the anti-TL1A
antibody with the
PBPK model from (b) such that after administration of the effective dose
regimen the
concentration of TL1A in a diseased tissue in the subject is below the
concentration of TL1A
in a corresponding tissue in a control subject without IBD. In one embodiment
of the
methods of this paragraph, the diseased subject has IBD.
[00342] In yet another aspect, provided herein is a method of determining an
effective
dose regimen for administering an anti-TL1A antibody to a diseased subject,
wherein the
method comprises: (a) receiving a parameter of TL1A over-production in the
diseased tissue
comparing to TL1A production in a normal reference tissue; (b) integrating the
parameter
received in (a) to a population pharmacokinetic (popPK) model; and (c)
determining the
effective dose regimen of the anti-TL1A antibody with the popPK model from (b)
such that
after administration of the effective dose regimen the concentration of TL1A
in a diseased
tissue in the subject is below the concentration of TL1A in a corresponding
tissue in a control
subject without IBD. In one embodiment of the methods of this paragraph, the
diseased
subject has IBD.
1003431 The parameter of TL1A over-production in the dose determination
methods
reflects the over-production of TL1A in the diseased tissues in affected
patients, e.g. UC or
CD patients. In some embodiments, the parameter of TL1A over-production is 10,
15,20,
25, 30, 35, 40, 45, 50, 55, 60,65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130,
140, 150, 160,
170, 180, 190,200 or more fold over-production comparing to TL1A production in
the
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normal reference tissue. In certain embodiments, the parameter of TL1A over-
production can
be various percentages or folds reflecting the over-production of TL1A in the
diseased tissues
in affected patients, e.g. UC or CD patients. In one embodiment, the parameter
of TL1A
over-production is up to or about 5 fold over-production comparing to TL1A
production in
the normal reference tissue. In one embodiment, the parameter of TL1A over-
production is
up to or about 10 fold over-production comparing to IL production in the
normal
reference tissue. In one embodiment, the parameter of TL1A over-production is
up to or
about 15 fold over-production comparing to TL1A production in the normal
reference tissue.
In one embodiment, the parameter of TL1A over-production is up to or about 20
fold over-
production comparing to TL1A production in the normal reference tissue. In one
embodiment, the parameter of TL1A over-production is up to or about 25 fold
over-
production comparing to TL1A production in the normal reference tissue. In one
embodiment, the parameter of TL1A over-production is up to or about 30 fold
over-
production comparing to TL1A production in the normal reference tissue. In one
embodiment, the parameter of TL1A over-production is up to or about 35 fold
over-
production comparing to TL1 A production in the normal reference tissue. In
one
embodiment, the parameter of TL1A over-production is up to or about 40 fold
over-
production comparing to TL1A production in the normal reference tissue. In one
embodiment, the parameter of TL1A over-production is up to or about 45 fold
over-
production comparing to TL1A production in the normal reference tissue. In one
embodiment, the parameter of TL1A over-production is up to or about 50 fold
over-
production comparing to TL1A production in the normal reference tissue. In one
embodiment, the parameter of TL1A over-production is up to or about 55 fold
over-
production comparing to TL1A production in the normal reference tissue. In one
embodiment, the parameter of TL1A over-production is up to or about 60 fold
over-
production comparing to TL1A production in the normal reference tissue. In one
embodiment, the parameter of TL1A over-production is up to or about 65 fold
over-
production comparing to TL IA production in the normal reference tissue. In
one
embodiment, the parameter of TL1A over-production is up to or about 70 fold
over-
production comparing to TL1A production in the normal reference tissue. In one
embodiment, the parameter of TL1A over-production is up to or about 75 fold
over-
production comparing to TL1A production in the normal reference tissue. In one
embodiment, the parameter of TL1A over-production is up to or about 80 fold
over-
production comparing to TL1A production in the normal reference tissue. In one
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embodiment, the parameter of TL1A over-production is up to or about 85 fold
over-
production comparing to TL1A production in the normal reference tissue. In one
embodiment, the parameter of TL1A over-production is up to or about 90 fold
over-
production comparing to TL1A production in the normal reference tissue. In one
embodiment, the parameter of TL1A over-production is up to or about 95 fold
over-
production comparing to TL1A production in the normal reference tissue. In one
embodiment, the parameter of TL IA over-production is up to or about 100 fold
over-
production comparing to TL1A production in the normal reference tissue. In one
embodiment, the parameter of TL1A over-production is up to or about 110 fold
over-
production comparing to TL1A production in the normal reference tissue. In one
embodiment, the parameter of TL1A over-production is up to or about 120 fold
over-
production comparing to TL1A production in the normal reference tissue. In one
embodiment, the parameter of TL1A over-production is up to or about 130 fold
over-
production comparing to TL1A production in the normal reference tissue. In one
embodiment, the parameter of TL1A over-production is up to or about 140 fold
over-
production comparing to TL1A production in the normal reference tissue. In one
embodiment, the parameter of TL1A over-production is up to or about 150 fold
over-
production comparing to TL1A production in the normal reference tissue. In one
embodiment, the parameter of TL1A over-production is up to or about 160 fold
over-
production comparing to TL1A production in the normal reference tissue. In one
embodiment, the parameter of TL over-production is up to or about 170 fold
over-
production comparing to TL1A production in the normal reference tissue. In one
embodiment, the parameter of TL1A over-production is up to or about 180 fold
over-
production comparing to TLI A production in the normal reference tissue. In
one
embodiment, the parameter of TL1A over-production is up to or about 190 fold
over-
production comparing to TL1A production in the normal reference tissue. In one
embodiment, the parameter of TL1A over-production is up to or about 200 fold
over-
production comparing to TL1A production in the normal reference tissue.
1003441 The step (a) in the dose determination methods provided herein
including in this
Section (Section 4.6) can receive additional parameters, such as the rate of
association and
dissociation between the anti-TL1A antibodies and TL1A. In one embodiment of
the method
step (a) further comprises receiving association rate of the antibody to TL1A
(IC on_mAb),
dissociation rate of the antibody from TL1A (koff-niAb), synthesis rate of
TL1A in normal
tissue (ksyn-nonnal), synthesis rate of TL1A in diseased tissue (ksyn-
chsease), and/or degradation
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rate of TL1A (k deg_
total-TL 1A)= In one embodiment, the association rate of the antibody to
TL1A (kontnAb) comprises the association rate of the antibody to monomeric
TL1A (kon_
monomer) and association rate of the antibody to trimeric TL1A (1( ontrimer).
In one embodiment,
the dissociation rate of the antibody from TL1A (kofr_mAb) comprises the
dissociation rate of
the antibody from monomeric TL1A (k off-monomer) and dissociation rate of the
antibody from
trimeric TL1A (k off-tri mer). In one embodiment, the degradation rate of TL1A
(kdeg-total-TT 1 A)
comprises degradation rate of monomeric TL1A (kdeg_TLIA-monomet) and
degradation rate of
trimeric TL1A (kdeg-nAA-rnmer)= In one embodiment, the association rate of the
antibody to
TL1A (kon_niAb) comprises the association rate of the antibody to monomeric
TL1A (kon_
monomer) and association rate of the antibody to trimeric TL1A (kontnmer1, and
the dissociation
f
rate of the antibody from TL1A (koff_mAb) comprises the dissociation rate of
the antibody from
monomeric TL1A (koff_monomer) and dissociation rate of the antibody from
trimeric TL1A (koff.
(rimer). In one embodiment, the association rate of the antibody to TL1A
(kon_mAb) comprises
the association rate of the antibody to monomeric TL1A (k on-monomer) and
association rate of
the antibody to trimeric TL1A (koõ.ni 1 and the degradation rate of TL1A (k
deg_
met, / total-
TL 1A)
comprises degradation rate of monomeric TL1 A (kdog-TL1A-monomet) and
degradation rate of
trimeric TL1A (IC deg-TL1A-nimer). In one embodiment, the dissociation rate of
the antibody from
TL1A (korr_mAb) comprises the dissociation rate of the antibody from monomeric
TL1A (k off.
monomer) and dissociation rate of the antibody from trimeric TL1A (k off-
Ulmer), and the
degradation rate of TL1A (1C deg-total-IL i A) comprises degradation rate of
monomeric TL1A
(kdeg-miA-monomer) and degradation rate of trimeric TL1A (kdeg-TL1A-ttimer)=
In one embodiment,
the association rate of the antibody to TL1A (koo.mAb) comprises the
association rate of the
antibody to monomeric TL1 A (kon-monomer) and association rate of the antibody
to trimeric
'TL1 A (kontnni,), the dissociation rate of the antibody from TL1 A (koff-mAb)
comprises the
dissociation rate of the antibody from monomeric TL1A (koff_monornõ) and
dissociation rate of
the antibody from trimeric TL1A (kofc_nime,), and/or the degradation rate of
TL1A (kdeg.total-
TUA) comprises degradation rate of monomeric TL1A (kdeg-miA-monomer) and
degradation rate
of trimeric TL I A (kdeg-TL1 A -tri mei)=
1003451 Additionally, the dose determination methods can include additional
parameters of
the anti-TL1A antibody binding to proteins other than the TL1A ligand, such as
the
parameters of the anti-TL1A antibodies or antigen binding fragments binding to
FcRn. In
some embodiments, the step (a) of the dose determination methods further
comprises
receiving association rate of the antibody to FoRn receptor (k on-mAb-FeRn),
dissociation rate of
the antibody from FcRn (koff- mAb-FcRn), association rate of the antibody-
monomeric-TL1A
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complex to FcRn receptor (koõ.(mAb-monoTL1A)-FcRA dissociation rate of the
antibody -
monomeric-TL1A complex from FcRn (koff_(mAb -mono TL 1A)-FcRn), association
rate of the
antibody-trimeric-TLIA complex to FcRn receptor (IC on-(mAb-triTL1A)-FcRn),
and/or dissociation
rate of the antibody-trimeric-TL1A complex from FcRn (koff-(mAb-niTL1A)-FcRn).
In one
embodiment, the step (a) of the dose determination methods further comprises
receiving
association rate of the antibody to FcRn receptor (k on -m Ab-FcR n), and/or
dissociation rate of the
antibody from FcRn (koff- mAb-FcRn). In another embodiment, the step (a) of
the dose
determination methods further comprises receiving association rate of the
antibody-
monomeric-TL I A complex to FcRn receptor (( on-(mAb -monoTL 1A)-FcRn), and/or
dissociation rate
of the antibody-monomeric-TL1A complex from FcRn (koff-(mAb-monomim-FcRn). In
yet another
embodiment, the step (a) of the dose determination methods further comprises
receiving
association rate of the antibody-trimeric-TL1A complex to FcRn receptor (k
on.(mAb -tnTL 1A)-
FcRn), and/or dissociation rate of the antibody -trimeric-TL 1 A complex from
FcRn (k off-(mAb -
trILL 1A)-FcRn) = In a further embodiment, the step (a) of the dose
determination methods further
comprises receiving association rate of the antibody-monomeric-TL1A complex to
FcRn
receptor (kon_(mAb-monoTL1A)-FcRn), dissociation rate of the antibody -
monomeric-TL1A complex
from FcRn (koff-(uAb-monomiA)-FcRO, association rate of the antibody -trimeric-
TL1A complex to
FcRn receptor (kon-(m AbTL1 A)-FcRn), and/or dissociation rate of the antibody-
trimeric-TL1A
complex from FcRn (koff-(mAb -triTL 1A)-FcRn) =
[00346] Alternatively, in some embodiments, the step (a) of the dose
determination
methods further comprises receiving association rate of the antibody to FcRn
receptor (k0
mAb -P cRn), dissociation rate of the antibody from FcRn (koff- mAb-F citn),
association rate of the
antibody-TLIA complex to FcRn receptor (koõ.(mAb_Thim_FcRõ), and/or
dissociation rate of the
antibody-TL1 A complex from FcRn (k off-(mAb-TL1A)-FcRn). In one embodiment,
the association
rate of the antibody- TL1A complex to FcRn receptor (kon-(mAb-mim-FeRn)
comprises
association rate of the antibody-monomeric-TL1A complex to FcRn receptor
(koõ.(mAb-
monomiA)-FcRO and association rate of the antibody-trimeric-TL1A complex to
FcRn receptor
(kon -(m Ab TL1 A)-FcR IA In one embodiment, the dissociation rate of the
antibody- TL1A
complex from FcRn (k0ff-(mAb-TL1A)-FcRn) comprises dissociation rate of the
antibody-
monomeric-TL1A complex from FcRn (koff-(mAb-mono ip)-rcRO and dissociation
rate of the
antibody-trimeric-TL1A complex from FcRn off.(mAb
FcRn) = In another embodiment,
the association rate of the antibody- TLIA complex to FcRn receptor (k0n-(mAb-
TL1A)-FcRn)
comprises association rate of the antibody-monomeric-TL1A complex to FcRn
receptor (IC on-
(mAb -monoTLIA)-FcRn) and association rate of the antibody -trimeric-TL1A
complex to FcRn
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receptor (koõ.(mAbTL1A)-FcRA and/or wherein the dissociation rate of the
antibody- TL1A
complex from FcRn (koff-(nAb-TL1A)-FcRO comprises dissociation rate of the
antibody-
monomeric-TL1A complex from FcRn (koff-(mAb -mono TL 1A)-FeRn) and
dissociation rate of the
antibody-trimeric-TL1A complex from FcRn (k off-(mAb -ttiTL 1A)-FeRn) =
1003471 Similarly, the dose determination methods can include
additional parameters such
as the parameters of degradation rate of the complex between the anti-TL1A
antibodies or
antigen binding fragments and FcRn. In one embodiment, the step (a) of the
dose
determination methods further comprises receiving clearance rate of FcRn
receptor bound by
the antibody (kdeg-mAb-FeRn). In one embodiment, the clearance rate of FcRn
receptor bound
by the antibody (kdeg-mAb-FcRil) further comprises clearance rate of the
antibody to FcRn bound
by the antibody-monomeric-TL1A complex (kdeg-(mAb-monoTL1A)-FeRn) and
clearance rate of
FcRn receptor bound by the antibody -trimeric-TL1A complex (k deg-(mAb -triTL
1A)-FcRn) =
1003481 Alternatively, in one embodiment, the step (a) of the dose
determination methods
further comprises receiving clearance rate of FcRn receptor bound by the
antibody (k deg-mAb-
FcRõ), clearance rate of the antibody to FcRn bound by the antibody -monomeric-
TL1A
complex (kdeg-(mAb-mottoT1-1A)-FeRo), and/or clearance rate of FcRn receptor
bound by the
antibody-trimeric-TL1A complex (kdeg-(mAbtriTL1A)-FcRn). In one embodiment,
the step (a) of
the dose determination methods further comprises receiving clearance rate of
FcRn receptor
bound by the antibody (1(deg_mAb-FeRn). In one embodiment, the step (a) of the
dose
determination methods further comprises receiving clearance rate of the
antibody to FcRn
bound by the antibody -monomeric-TL1A complex (kdeg-(mAb-monoTL1A)-FcRn). In
one
embodiment, the step (a) of the dose determination methods further comprises
receiving
clearance rate of FcRn receptor bound by the antibody -trimeric-TL1A complex
(kdeg(mAb-
triTL1A)-FeRn). In one embodiment, the step (a) of the dose determination
methods further
comprises receiving clearance rate of FcRn receptor bound by the antibody
(kdog-mAb-FeRn) and
clearance rate of the antibody to FcRn bound by the antibody-monomeric-TL1A
complex
(kdeg-(mAb-monomiA)-FcRii). In one embodiment, the step (a) of the dose
determination methods
further comprises receiving clearance rate of FcRn receptor bound by the
antibody (kdeg-mAb-
FcRn) and clearance rate of FcRn receptor bound by the antibody-trimeric-TL1A
complex
(cdeg-(mAb -triTL 1A)-FcRo) = In one embodiment, the step (a) of the dose
determination methods
further comprises receiving clearance rate of the antibody to FcRn bound by
the antibody-
monomeric-TL1A complex (kdeg-(m Ab noTL 1 A)-FeRn) and clearance rate of FcRn
receptor
bound by the antibody-trimeric-TL1A complex (kdeg-(mAb -triTL 1A)-F cRn) = In
one embodiment,
the step (a) of the dose determination methods further comprises receiving
clearance rate of
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FcRn receptor bound by the antibody (k deg_mAb-FcRA clearance rate of the
antibody to FcRn
bound by the antibody-monomeric-TL1A complex (k deg-(mAb -mono TL 1A)-FcRA and
clearance rate
of FcRn receptor bound by the antibody -trimeric-TL1A complex
(kdeg.(mAbtrimiA).FeRn).
1003491 In addition, in various embodiments of the dose determination methods
provided
herein, including in this Section (Section 4.6), the step (a) in the dose
determination methods
further comprises receiving the rate of TL1A trimerization (k on -TT .1 A -
monomer-to-ttimer) and/or the
rate of TL I A monomerization (koff-TL TA-tti mer-to-mono met). In one
embodiment, the step (a) in the
dose determination methods further comprises receiving the rate of TLIA
trimerization on_
TL 1A-monomer-to -tnmer)= In another embodiment, the step (a) in the dose
determination methods
further comprises receiving the rate of TL1A monomerization (koff-miAtiimer-to-
monomer). In yet
another embodiment, the step (a) in the dose determination methods further
comprises
receiving the rate of TL1A trimerization (koo_Th A-monomer-to trimer) and the
rate of TL1A
monomerization off-TL1A-ttimer-to-mo /tomer) =
1003501 The term rate of TLIA trimerization refers to the kinetic rate at
which TLIA
monomers self-associate to form TLIA trimer. The term rate of TLIA
monomerization
refers to the kinetic rate at which TL1 A trim er dissociates into TL1 A
monomers.
1003511 The various parameters in the dose determination methods can be
identical or
different. The various parameters in the dose determination methods can also
be related by a
range, a fold difference in value, and/or by a specific difference in value.
In one embodiment
of the various dose determination methods provided herein, k on-monomer and
kontnmer are
identical or different. In one embodiment of the various dose determination
methods
provided herein, koft_monomerand kart., are identical or different. In one
embodiment of the
various dose determination methods provided herein, kdeg_mollomerand kdegtilm,
are identical or
different. In one embodiment of the various dose determination methods
provided herein,
kon-(mAb -mono TL 1A)-FeRn and kon-(mAb-ttilt TA)-FoRo are identical or
different. In one embodiment of
the various dose determination methods provided herein, k
on-(mAb-monoTL A)-
on-mAb -BATT and k
FcRn are identical or different. In one embodiment of the various dose
determination methods
provided herein, koõ-mAb-FcRn and kon-0,,Ab-tiiTL 1 A)-FcR n are identical or
different. In one
embodiment of the various dose determination methods provided herein, k off-
(mAb -monoTL 1A)-
FcRn and k0ff-(113Ab-tta1L1A)-FcRn are identical or different. In one
embodiment of the various dose
determination methods provided herein, k offrnAbFRn and k _
off-(rnAb-rnoTL no1A)-FcRn are identical or
-c
different. In one embodiment of the various dose determination methods
provided herein,
koff- mAb-FcRn and koff-(mAb-triTLIA)-FcRn are identical or different. In one
embodiment of the
various dose determination methods provided herein, k deg-(mAb-monoTLIA)-FcRn
and kcieg-(mAb-
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hiTL1A)-FcRn are identical or different. In one embodiment of the various dose
determination
methods provided herein, kdeg-mithFcRn and k deg-(mikbMTL-1A)-FcRn are
identical or different. In
-
one embodiment of the various dose determination methods provided herein,
kdeg_mAb_FeRn and
kdeg-(mAb-monoTL1A)-FeRn are identical or different. In one embodiment of the
various dose
determination methods provided herein, the parameters received in the dose
determination
methods can have any combination of the relationship as described herein,
including in this
paragraph.
[00352] As is clear from the description herein, the diseased tissue
overproduces TL1A
than a normal tissue. As already provided above, the diseased tissue
overproduces TL1A
comparing to normal reference tissue and the parameter of TL1A over-production
can be 10,
15, 20, 25, 30, 35, 40,45, 50,55, 60,65, 70,75, 80, 85, 90,95, 100, 110, 120,
130, 140, 150,
160, 170, 180, 190,200 or more fold over-production comparing to TL1A
production in the
normal reference tissue. Therefore, the ksyn-disease can be higher than ksyn-
nommi by various
percentages or folds. In one embodiment of the dose determination methods, k
syn-disease iS UP
to or about 5, 10, 15, 20,25, 30,35, 40,45, 50, 55, 60,65, 70,75, 80,85,
90,95, 100, 110,
120, 130, 140, 150, 160, 170,180, 190, 200, or more fold of k syn-normai. In
one embodiment of
the dose determination methods, ksyn-disease is up to or about 5 fold of ksyn-
nonnal. In one
embodiment of the dose determination methods, ksyn-disease is up to or about
10 fold of ksyn-
nonnai. In one embodiment of the dose determination methods, ksya_aisease is
up to or about 15
fold of ksyn-nomial. In one embodiment of the dose determination methods, ksyn-
disease is up to or
about 20 fold of ksyn-nonnat. In one embodiment of the dose determination
methods, ksyn-disease
is up to or about 25 fold of ksyn-nonnat. In one embodiment of the dose
determination methods,
ksyn-chsease is up to or about 30 fold of ksyn-nonnai. In one embodiment of
the dose determination
methods, ksya_disease is up to or about 35 fold of k syn_nonnal. In one
embodiment of the dose
determination methods, kva_discase is up to or about 40 fold of ksyn_nonnai.
In one embodiment of
the dose determination methods, ksyn_disease is up to or about 45 fold of
ksyn_aollaai. In one
embodiment of the dose determination methods, ksyn-disease is up to or about
50 fold of k syn-
normal In one embodiment of the dose determination methods, ksyõ.msease is up
to or about 55
fold of ksyn-nomiai. In one embodiment of the dose determination methods, ksyn-
disease is up to or
about 60 fold of ksyn-normai. In one embodiment of the dose determination
methods, ksyn-disease
is up to or about 65 fold of ksyn.nonnal. In one embodiment of the dose
determination methods,
ksyn-disease is up to or about 70 fold of ksyn-normai. In one embodiment of
the dose determination
methods, ksyn-disease is up to or about 75 fold of ksyn-nomiat. In one
embodiment of the dose
determination methods, ksya_disease is up to or about 80 fold of ksyn_nonnat.
In one embodiment of
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the dose determination methods, ksyn-disease is up to or about 85 fold of ksyn-
normal= In one
embodiment of the dose determination methods, ksyn-disease is up to or about
90 fold of ksyn.
nonnal. In one embodiment of the dose determination methods, ksyn-disease is
up to or about 95
fold of ksyn-nomiai. In one embodiment of the dose determination methods, ksyn-
disease is up to or
about 100 fold of ksynmal. In one embodiment of the dose determination
methods, ksyn-disease
is up to or about 110 fold of k vn-nonnal = In one embodiment of the dose
determination
methods, ksyn-Msease is up to or about 120 fold of ksyn-normai. In one
embodiment of the dose
determination methods, ksyn.thsease is up to or about 130 fold of ksyn_nonnal.
In one embodiment
of the dose determination methods, ksyn-disease is up to or about 140 fold of
ksyn-normal= In one
embodiment of the dose determination methods, ksyn-disease is up to or about
150 fold of ksyn-
nonnal. In one embodiment of the dose determination methods, ksyn_disens, is
up to or about 160
fold of ksyn_nonnal. In one embodiment of the dose determination methods, ksyn-
disease is up to or
about 170 fold of ksyn-nninini. In one embodiment of the dose determination
methods, ksyn-disease
is up to or about 180 fold of ksyn,nnai. In one embodiment of the dose
determination
methods, ksyn_disease is up to or about 190 fold of k syn-nonnal = In one
embodiment of the dose
determination methods, ksyn-disease is up to or about 200 fold of ksyn-mnnai.
1003531 Normal tissue, reference tissue, or normal reference tissue in the
methods
(including the methods provided in this Section (Section 4.6), such as methods
of
use/treatment and/or dose determination methods) refers to a tissue without
the pathology
from MD and/or without abnormal TL1A expression. In some embodiments of the
dose
determination methods, such normal tissue comprises or consists of a healthy
tissue (e.g.
tissue without IBD-related pathology and/or without abnormal TL1A expression)
from the
subject with MD. In certain embodiments of the dose determination methods,
such normal
tissue comprises or consists of a corresponding or reference tissue from a
subject without
MD, as already provided and described in further details in this Section
(Section 4.6).
1003541 The various parameters for whole-body Physiologically Based
Pharmacokinetic
("PBPK") in the dose determination methods, including the various rate
parameters, can be
such parameters already known and used in whole-body PBPK, for example as
described in
Jones H et al., American Association ofPharmaceutical Scientists Journal (AAPS
J.)2013
Apr;15(2):377-87; Dostalek, M et al., Clin Pharmacokinet, 2013 Feb;52(2):83 -
124; Li L et
al., AAPS J. 2014 Sep;16(5):1097-109; Nestorov I. Clin Pharmacokinet.
2003;42(10):883-
908. In some embodiments, the various whole-body PBPK parameters in the dose
termination methods, including the various rate parameters described in this
Section (Section
4.6), can have the value as described in Section 5. In other embodiments, the
various whole-
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body PBPK parameters in the dose termination methods, including the various
rate
parameters described in this Section (Section 4.6), can be determined as
described in Section
5.
[00355] Alternatively, the various parameters for Population Pharmacokinetic
("popPK")
model in the dose determination methods, including the various rate
parameters, can be such
parameters already known and used in popPK, for example as described in Mould
DR et al.,
CPT Pharmacometrics Syst Pharmacol. 200 Apr; 2(4): e38; Guidance for Industry
Population Pharmacokinetics, by U.S. Department of Health and Human Services
Food and
Drug Administration Center for Drug Evaluation and Research (CDER) Center for
Biologics
Evaluation and Research (CBER), February, 1999. In some embodiments, the
various popPK
parameters in the dose termination methods, including the various rate
parameters described
in this Section (Section 4.6), can have the value as described in Section 5.
In other
embodiments, the various popPK parameters in the dose termination methods,
including the
various rate parameters described in this Section (Section 4.6), can be
determined as
described in Section 5.
1003561 "Population pharmacokinetic model" or "popPK model" is a model
integrating the
mathematical simulations of the absorption, distribution, metabolism and
elimination of a
drug and their metabolites to fit and/or predict the drug concentrations among
a patient
population, wherein such model can fit and/or predict the observed time course
of drug
concentrations among the patient population receiving clinically relevant
doses of the drug
and variability in the drug concentrations among such patient population. Such
popPK model
can predict the time course of drug concentrations among the patient
populations receiving a
given dose, and thus can simulate and determine the dose for an intended drug
level in a
patient population. In some embodiments, the popPK model comprises or consists
of the
popPK model described in Section 5.
1003571 "Whole-body physiologically based pharmacokinetic model" or "whole-
body
PBPK model" is a model integrating and mapping the absorption, distribution,
metabolism
and elimination of a drug and their metabolites onto a physiologically
realistic compartmental
structure, including body tissues, fluids, organs, and/or systems. Such whole-
body PBPK
model can have two distinctive set of parameters: (i) a drug independent
subset, derived from
the underlying physiological processes (e.g. diffusion and transport), which
can be available
as known and practiced in the field or determined specifically for a specific
patient
population as known and practiced in the field; and (ii) a drug-specific
subset characterizing
the pharmacokinetic properties of the particular drug and derived from
clinical or preclinical
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studies. Such whole-body PBPK model can fit and/or predict the observed time
course of
drug concentrations in the patient receiving clinically relevant doses of the
drug. Such
whole-body PBPK model can predict the time course of drug concentrations in
the patient
receiving a given dose, and thus can simulate and determine the dose for an
intended drug
level in the patient. In some embodiments, the whole-body PBPK model comprises
or
consists of the whole-body PBPK model described in Section 5.
1003581 As is clear from the description, the dose determination method
provided herein
can be used to determine the effective dose, the induction regimen, and/or the
maintenance
regimen for the various embodiments of the methods of treatment, the methods
of reducing
TL1A concentration in a diseased tissue, and the methods of neutralizing
monomeric and
trimeric TL1A. Therefore, the various embodiments described herein for the
elements recited
in the dose determination methods are also provided for the dose determination
methods,
including the various embodiments on the anti-TL1A antibodies or antigen
binding fragments
(e.g. in this Section (Section 4.6) and Sections 4.2 and 5), those on the
effective dose (e.g. in
this Section (Section 4.6) and Section 5), those on the induction regimen
(e.g. in this Section
(Section 4.6) and Section 5), those on the maintenance regimen (e.g. in this
Section (Section
4.6) and Section 5), those on the diseased tissues, and/or those on the
corresponding or
reference tissues (e.g. in this Section (Section 4.6) and Section 5).
1003591 In some embodiments of the various methods provided herein, including
in this
Section (Section 4.6, e.g. each paragraph of Section 4.6), the concentration
of TL1A is the
concentration of free TL1A. In certain embodiments of the various methods
provided herein,
including in this Section (Section 4.6, e.g. each paragraph of Section 4.6),
the concentration
of TL1A in the diseased tissue referred to in the various methods is the
concentration of free
ml A in the diseased tissue. In some embodiments of the various methods
provided herein,
including in this Section (Section 4.6, e.g. each paragraph of Section 4.6),
the concentration
of TL1A in a corresponding tissue or reference tissue is the concentration of
free TL1A in the
corresponding tissue or reference tissue. In certain other embodiments of the
various
methods provided herein, including in this Section (Section 4.6, e.g. each
paragraph of
Section 4.6), the concentration of TL1A in the diseased tissue referred to in
the various
methods is the concentration of free TL1A in the diseased tissue and the
concentration of
TL1A in a corresponding tissue or reference tissue is the concentration of
free TL1A in the
corresponding tissue or reference tissue. As used herein, free TL1A means TL1A
not
neutralized or bound by the anti-TL1A antibody. Such free TL1A is the TL1A
that can
engage DR3 and trigger TL1A mediated signaling or functions.
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1003601 Methods disclosed herein provide methods of treating an inflammatory
disease or
condition in a subject by administering an anti-TL1A antibody described herein
to the
subject. In example embodiments, the inflammatory disease or condition is
inflammatory
bowel disease. In various embodiments, IBD is Crohn's Disease (CD) and/or
ulcerative
colitis (UC). In some embodiments, the IBD patient presents with fibrosis. In
some
embodiments, the IBD is a severe form of IBD. In some embodiments, the IBD is
a moderate
to severe form of IBD. In some embodiments, the IBD is a moderate form of IBD.
In various
other embodiments, the subject is determined to have an increased TL1A
expression. In some
embodiments, the administration of a therapeutically effective amount of an
anti-TL1A
antibody causes a decrease in TL1A in the subject treated. In example
embodiments, the anti-
TL1A antibody comprises any one of the anti-TL1A antibody embodiments provided
herein.
In some embodiments, the anti-TL1A antibody comprises antibody A, B, C, D, E,
F, G, H, I,
A2, B2, C2, D2, E2, F2, G2, H2, or 12. In some embodiments, the anti-TL1A
antibody
comprises any one of the antibodies of Table 1. As a non-limiting example, the
anti-TL1A
antibody comprises antibody A219.
1003611 In some embodiments, methods comprise treating patients with an anti-
TL1A
antibody comprising higher levels of TL1A as compared to patients who do not
have a
disease or condition herein. In some embodiments, methods comprise treating
patients with
an anti-TL1A antibody comprising higher levels of DR3 as compared to patients
who do not
have a disease or condition herein. For instance, the patients who do not have
a disease or
condition herein do not have inflammation and/or fibrosis. TL levels
include levels of
TL1A protein, RNA, and/or DNA in a biological sample from the subject.
1003621 The anti-TL1A antibodies described herein may substantially improve
outcomes
for IBD patients who are predisposed to increased TL1A expression. As an
example, the
patients are selected for treatment with an anti-TL1A antibody herein based on
increased
expression of TL1A in the patient as compared to a reference level (e.g., from
a subject who
does not have IBD). The patients may be selected for increased TL1A expression
as
determined by a genotyping assay to determine the presence of a genotype
associated with
increased TL1A expression. TL1A and nucleic acids encoding TL1A (Tumor
Necrosis Factor
Ligand Superfamily Member 15 (77VFSF15)) are provided as set forth by Entrez
Gene: 9966;
UniProtKB: 095150.
1003631 In some embodiments, a subject refers to any animal, including, but
not limited to,
humans, non-human primates, rodents, and domestic and game animals, which is
to be the
recipient of a particular treatment. Primates include chimpanzees, cynomolgus
monkeys,
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spider monkeys, and macaques, e.g., Rhesus. Rodents include mice, rats,
woodchucks,
ferrets, rabbits and hamsters. Domestic and game animals include cows, horses,
pigs, deer,
bison, buffalo, feline species, e.g., domestic cat, canine species, e.g., dog,
fox, wolf', avian
species, e.g., chicken, emu, ostrich, and fish, e.g., trout, catfish and
salmon. In various
embodiments, a subject can be one who has been previously diagnosed with or
identified as
suffering from or having a condition in need of treatment. In certain
embodiments, the subject
is a human. In various embodiments, the subject previously diagnosed with or
identified as
suffering from or having a condition may or may not have undergone treatment
for a
condition. In some embodiments, a subject can also be one who has not been
previously
diagnosed as having a condition (i.e., a subject who exhibits one or more risk
factors fora
condition). A "subject in need" of treatment for a particular condition can be
a subject having
that condition, diagnosed as having that condition, or at risk of developing
that condition. In
some embodiments, the subject is a "patient," that has been diagnosed with a
disease or
condition described herein. In some instances, the subject is suffering from a
symptom
related to a disease or condition disclosed herein (e.g., abdominal pain,
cramping, diarrhea,
rectal bleeding, fever, weight loss, fatigue, loss of appetite, dehydration,
and malnutrition,
anemia, or ulcers).
[00364] In some embodiments, the term "therapeutically effective amount"
refers to an
amount of an antibody effective to "treat" a disease or disorder in a subject
or mammal. In
some cases, therapeutically effective amount of the drug reduces the severity
of symptoms of
the disease or disorder. In some instances, the disease or disorder comprises
inflammatory
bowel disease (IBD), Crohn's disease (CD), or ulcerative colitis (UC). In some
instances, the
IBD, CD, and/or UC are severe or medically refractory forms of the IBD, CD,
and/or UC
Non-limiting examples of symptoms of IBD, CD, and/or UC include, but are not
limited to,
diarrhea, fever, fatigue, abdominal pain, abdominal cramping, inflammation,
ulceration,
nausea, vomiting, bleeding, blood in stool, reduced appetite, and weight loss.
[00365] In some embodiments, the terms, "treat" or "treating" as used herein
refer to both
therapeutic treatment and prophylactic or preventative measures (e.g., disease
progression),
wherein the object is to prevent or slow down (lessen)the targeted pathologic
condition.
Therapeutic treatment includes alleviating the condition and alleviating
symptoms of the
condition. In some aspects provided herein, subjects in need of treatment
include those
already with a disease or condition, as well as those susceptible to develop
the disease or
condition. The disease or condition may comprise an inflammatory disease or
condition.
[00366] The pharmaceutical compositions may be delivered in a therapeutically
effective
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amount. The precise therapeutically effective amount is that amount of the
composition that
will yield the most effective results in terms of efficacy of treatment in a
given subject. This
amount will vary depending upon a variety of factors, including but not
limited to the
characteristics of therapeutic compound (including activity, pharmacokinetics,
pharmacodynamics, and bioavailability), the physiological condition of the
subject (including
age, sex, disease type and stage, general physical condition, responsiveness
to a given dosage,
and type of medication), the nature of the pharmaceutically acceptable carrier
or carriers in
the formulation, and the route of administration. One skilled in the clinical
and
pharmacological arts will be able to determine a therapeutically effective
amount through
routine experimentation, for instance, by monitoring a subject's response to
administration of
a compound and adjusting the dosage accordingly. For additional guidance, see
Remington:
The Science and Practice ofPharmacy (Gennaro ed. 20th edition, Williams &
Wilkins PA,
USA) (2000).
1003671 For the treatment of the disease, the appropriate dosage of an
antibody depends on
the type of disease to be treated, the severity and course of the disease, the
responsiveness of
the disease, whether the antibody is administered for therapeutic or
preventative purposes,
previous therapy, and patient's clinical history. The dosage can also be
adjusted by the
individual physician in the event of any complication and at the discretion of
the treating
physician. The administering physician can determine optimum dosages, dosing
methodologies and repetition rates. The TL1A antibody can be administered one
time or over
a series of treatments lasting from several days to several months, or until a
cure is effected or
a diminution of the disease state is achieved (e.g, treatment or amelioration
of IBD
symptoms). The duration of treatment depends upon the subject's clinical
progress and
responsiveness to therapy. In certain embodiments, dosage is from 0.01 pg to
100 mg per kg
of body weight, and can be given once or more daily, weekly, monthly or
yearly.
1003681 In one aspect, a method of treating an inflammatory disease or
condition
comprises administering to a subject an anti-TL1A antibody. In some
embodiments, the
subject is administered a dose of up to about 1000 mg. In some embodiments,
the subject is
administered a dose from about 150 mg to about 1000 mg. In some cases, the
dose is about
150 mg to about 900 mg, about 150 mg to about 800 mg, about 150 mg to about
700 mg,
about 150 mg to about 600 mg, about 150 mg to about 500 mg, about 150 mg to
about 400
mg, about 150 mg to about 300 mg, about 150 mg to about 200 mg, about 160 mg
to about
1000 mg, about 160 mg to about 900 mg, about 160 mg to about 800 mg, about 160
mg to
about 700 mg, about 160 mg to about 600 mg, about 160 mg to about 500 mg,
about 160 mg
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to about 400 mg, about 160 mg to about 300 mg, about 160 mg to about 200 mg,
about 170
mg to about 1000 mg, about 170 mg to about 900 mg, about 170 mg to about 800
mg, about
170 mg to about 700 mg, about 170 mg to about 600 mg, about 170 mg to about
500 mg,
about 170 mg to about 400 mg, about 170 mg to about 300 mg, about 170 mg to
about 200
mg, about 175 mg to about 1000 mg, about 175 mg to about 900 mg, about 175 mg
to about
800 mg, about 175 mg to about 700 mg, about 175 mg to about 600 mg, about 175
mg to
about 500 mg, about 175 mg to about 400 mg, about 175 mg to about 300 mg,
about 175 mg
to about 200 mg, about 180 mg to about 1000 mg, about 180 mg to about 900 mg,
about 180
mg to about 800 mg, about 180 mg to about 700 mg, about 180 mg to about 600
mg, about
180 mg to about 500 mg, about 180 mg to about 400 mg, about 180 mg to about
300 mg,
about 180 mg to about 200 mg, about 190 mg to about 1000 mg, about 190 mg to
about 900
mg, about 190 mg to about 800 mg, about 190 mg to about 700 mg, about 190 mg
to about
600 mg, about 190 mg to about 500 mg, about 190 mg to about 400 mg, about 190
mg to
about 300 mg, about 190 mg to about 200 mg, about 200 mg to about 1000 mg,
about 200 mg
to about 900 mg, about 200 mg to about 800 mg, about 200 mg to about 700 mg,
about 200
mg to about 600 mg, about 200 mg to about 500 mg, about 200 mg to about 400
mg, or about
200 mg to about 300 mg. In some cases, the dose is about 150 mg, about 160 mg,
about 170
mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220, about
230 mg,
about 240 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about
450 mg,
about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about
750 mg,
about 800 mg, about 850 mg, about 900, about 950 mg, or about 1000 mg.
[00369] In some cases, an anti-TLI A is administered in a fixed dose, e.g.,
about 150 mg,
about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about
210 mg,
about 220, about 230 mg, about 240 mg, about 250 mg, about 300 mg, about 350
mg, about
400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg,
about 700
mg, about 750 mg, about 800 mg, about 850 mg, about 900, about 950 mg, or
about 1000 mg
In some cases, an anti-TLIA is administered based on weight (kg) of the
subject. For
instance, the anti-TLIA is administered at a dose of about 0.15 mg/kg to about
20 mg/kg, or
about 0.15 mg/kg, about 1.0 mg/kg, about 1.5 mg/kg, about 2.0 mg/kg, about 2.5
mg/kg,
about 3.0 mg/kg, about 3.5 mg/kg, about 4.0 mg/kg, about 4.5 mg/kg, about 5.0
mg/kg, about
5.5 mg/kg, about 6.0 mg/kg, about 6.5 mg/kg, about 7.0 mg/kg, about 7.5 mg/kg,
about 8.0
mg/kg, about 8.5 mg/kg, about 9.0 mg/kg, about 9.5 mg/kg, about 10.0 mg/kg,
about 11
mg/kg, about 12 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about
16 mg/kg,
about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, or about 20 mg/kg.
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1003701 In some embodiments, a dose of anti-TL1A is administered
subcutaneously. In
some embodiments, a dose of anti-TL1A is administered intravenously.
1003711 For subcutaneous injection, the dose may be administered in one or
multiple
injections. As a non-limiting example, a dose comprising about 800 mg of anti-
TL1A may be
administered in about 2, 3, 4, or 5 injections. As a further example, the dose
comprising about
800 mg of anti-TL1A antibody is administered in about 4 injections of about
200 mg/mL. In
some embodiments, the dose may be administered in one injection. For example,
a dose
comprising about 175-300 mg anti-TL1A is administered in one injection of
about 175-250
mg/mL. As another example, a dose comprising about 175-300 mg anti-TL1A is
administered in one injection of about 175-200 mg/mL.
1003721 In some embodiments, a dose and/or injection of anti-TL1A is
administered in a
volume of less than about 3 mL, less than about 2.9 mL, less than about 2.8
mL, less than
about 2.7 mL, less than about 2.6 mL, less than about 2.5 mL, less than about
2.4 mL, less
than about 2.3 mL, less than about 2.2 mL, less than about 2.1 mL, less than
about 2 mL, less
than about 1.9 mL, less than about 1.8 mL, less than about 1.7 mL, less than
about 1.6 mL,
less than about 1.5 mL, less than about 1.4 mL, less than about 1.3 mL, less
than about 1.2
mL, less than about 1.1 mL, less than about 1.0 mL, less than about 0.9 mL,
less than about
0.8 mL, or less than about 0.7 mL. The volume may be at least about 0.5 mL.
The volume
may be about 0.5 mL to about 3 mL, about 0.5 mL to about 2.9 mL, about 0.5 mL
to about
2.8 mL, about 0.5 mL to about 2.7 mL, about 0.5 mL to about 2.6 mL, about 0.5
mL to about
2.5 mL, about 0.5 mL to about 2.4 mL, about 0.5 mL to about 2.3 mL, about 0.5
mL to about
2.2 mL, about 0.5 mL to about 2.1 mL, about 0.5 mL to about 2 mL, 0.5 mL to
about 1.9 mL,
0.5 mL to about 1.8 mL, 0.5 mL to about 1.7 mL, 0.5 mL to about 1.6 mL, about
0.5 mL to
about 1.0 mL, about 0.5 mL to about 0.9 mL, about 0.5 mL to about 0.8 mL,
about 0.6 mL to
about 3 mL, about 0.6 mL to about 2.9 mL, about 0.6 mL to about 2.8 mL, about
0.6 mL to
about 2.7 mL, about 0.6 mL to about 2.6 mL, about 0.6 mL to about 2.5 mL,
about 0.6 mL to
about 2.4 mL, about 0.6 mL to about 2.3 mL, about 0.6 mL to about 2.2 mL,
about 0.6 mL to
about 2.1 mL, about 0.6 mL to about 2.0 mL, about 0.6 mL to about 1.9 mL,
about 0.6 mL to
about 1.8 mL, about 0.6 mL to about 1.7 mL, about 0.6 mL to about 1.6 mL,
about 0.6 mL to
about 1.5 mL, about 0.6 mL to about 1.4 mL, about 0.6 mL to about 1.3 mL,
about 0.6 mL to
about 1.2 mL, about 0.6 mL to about 1.1 mL, about 0.6 mL to about 1.0 mL,
about 0.6 mL to
about 0.9 mL, about 0.6 mL to about U.S mL, about 0.7 mL to about 3 mL, about
0.7 mL to
about 2.9 mL, about 0.7 mL to about 2.8 mL, about 0.7 mL to about 2.7 mL,
about 0.7 mL to
about 2.6 mL, about 0.7 mL to about 2.5 mL, about 0.7 mL to about 2.4 mL,
about 0.7 mL to
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about 2.3 mL, about 0.7 mL to about 2.2 mL, about 0.7 mL to about 2.1 mL,
about 0.7 mL to
about 2.0 mL, about 0.7 mL to about 1.9 mL, about 0.7 mL to about 1.8 mL,
about 0.7 mL to
about 1.7 mL, about 0.7 mL to about 1.6 mL, about 0.7 mL to about 1.5 mL,
about 0.7 mL to
about 1.4 mL, about 0.7 mL to about 1.3 mL, about 0.7 mL to about 1.2 mL,
about 0.7 mL to
about 1.1 mL, about 0.7 mL to about 1.0 mL, about 0.7 mL to about 0.9 mL, or
about 0.7 mL
to about 0.8 mL. In some embodiments, the concentration of anti-TL1A in each
dose and/or
injection is about or D-eater than about 155, 160, 165, 170, 175, 180, 185,
190, 195, 200, 205,
210, 215, 220, or 225 mg/mL of anti-TL1A.
1003731 In some embodiments, the method comprises administering more than one
dose of
anti-TL1A. Subsequent doses may have the same amount, less than, or greater
than the
amount of anti-TL1A as the first dose. A subsequent dose may be administered
about 1, 2, 3,
4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21,22, 23,24,
25,26, 27,28, 29,30,
or 31 days after the previous dose. A subsequent dose may be administered
about 1, 2, 3, or 4
weeks after the previous dose. The one or more doses may be about 1, 2, 3, 4,
5, 6, 7, 8, 9, 10,
11, 12, 13, 14, 15, 16,17, 18, 19, or 20 doses. In anon-limiting example, anti-
TL1A is
administered in about 6 doses, optionally every other week. In another non -
limiting example,
anti-TL1A is administered in about 12 doses, optionally weekly. In some
embodiments, the
one or more doses of anti-TL1A are administered during an induction period.
The induction
period may be about 6, 7, 8,9, 10, 11, 12, 13, 14, or 15 weeks. As a non-
limiting example,
the induction period is about 12 weeks. After the induction period, the
subject may be further
treated, e.g., with additional doses of anti-TL1A in a maintenance period. In
some
embodiments, the maintenance period comprises administering anti-TL1A every 1,
2, 3, 4, 5,
6, or 7 days, or every 1, 2, 3, or 4 weeks. In an example embodiment, the
maintenance period
comprises administering anti-TL1A every 2 or 4 weeks. In a non-limiting
embodiment, the
first dose is an i.v. dose, and one or more subsequent doses is a s.c. dose.
In some
embodiments, one or more doses are i.v. doses. In some embodiments, one or
more doses are
s.c. doses. In some embodiments, an induction period comprises i.v.
administration. In some
embodiments, a maintenance period comprises s.c. administration.
1003741 In some embodiments, the method comprise administering to the subject
a first
dose of anti-TL1A. In some embodiments, the dose comprises about 250 mg to
about 1000
mg of anti-TL1A, about 400 mg to about 600 mg, about 700 mg to about 800 mg,
or about
250 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg,
about 425
mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg,
about 575 mg
about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about
725 mg,
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about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about
875 mg,
about 900 mg, about 925 mg, about 950 mg or about 1000 mg anti-TLIA. In some
embodiments, the first dose comprises about 800 mg anti-TLIA. In example
embodiments,
the first dose comprises about 800 mg anti-TLIA administered subcutaneously.
In example
embodiments, the first dose comprises about 500 mg anti-TLIA administered
intravenously.
1003751 In some embodiments, the method comprises administering to a subject
the first
dose of anti-TL1A at a first time point and a second dose of anti-TLIA at a
second time
point. In some cases, the second time point is about 1, 2, 3, 4, 5, 6, 7, 8,
9, 10, 11, 12, 13, 14,
15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, 29, 30, or 31 days
after the first time
point. In some cases, the second time point is about 1, 2, 3, or 4 weeks after
the first time
point. In some cases, the second dose comprises the same amount of anti-TLI A
as the first
dose. In some cases, the second dose comprises a different amount of anti-TL1A
as the first
dose. In some cases, the second dose comprises about 150 mg to about 700 mg,
about 150 mg
to about 300 mg, about 150 mg to about 225 mg, about 175 mg to about 225 mg,
about 400
mg to about 600 mg, about 450 mg to about 550 mg, about 475 mg to about 525
mg, or about
150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg,
about 210
mg, about 220, about 230 mg, about 240 mg, about 250 mg, about 300 mg, about
350 mg,
about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about
650 mg, or
about 700 mg anti-TL1A. In example embodiments, the second dose comprises
about 175 -
300 mg anti-TLIA administered subcutaneously about 1 week after the first
dose. In example
embodiments, the second dose comprises about 500 mg anti-TL1A administered
intravenously about 2 weeks after the first dose.
1003761 In some embodiments, the method comprises administering to the subject
a third
dose of anti-TL1A at a third time point. In some cases, the third time point
is about 1, 2, 3, 4,
5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19,20, 21,22, 23,24, 25,26,
27,28, 29,30, or
31 days after the second time point. In some cases, the third time point is
about 1, 2, 3, or 4
weeks after the second time point. In some cases, the third dose comprises the
same amount
of anti-TL1A as the second dose. In some cases, the third dose comprises a
different amount
of anti-TLI A as the second dose. In some cases, the third dose comprises
about 150 mg to
about 700 mg, about 150 mg to about 300 mg, about 150 mg to about 225 mg,
about 175 mg
to about 225 mg, about 400 mg to about 600 mg, about 450 mg to about 550 mg,
about 475
mg to about 525 mg, or about 150 mg, about 160 mg, about 170 mg, about 180 mg,
about 190
mg, about 200 mg, about 210 mg, about 220, about 230 mg, about 240 mg, about
250 mg,
about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about
550 mg,
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about 600 mg, about 650 mg, or about 700 mg anti-TL1A. In example embodiments,
the third
dose comprises about 175-300 mg anti-TL1A administered subcutaneously about 1
week
after the second dose. In example embodiments, the third dose comprises about
500 mg anti-
TL1A administered intravenously about 2 weeks after the second dose.
1003771 In some embodiments, the method comprises administering to the subject
a fourth
dose of anti-TL1A at a fourth time point. In some cases, the fourth time point
is about 1, 2, 3,
4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21,22, 23,24,
25,26, 27,28, 29,30,
or 31 days after the third time point. In some cases, the fourth time point is
about 1, 2, 3, or 4
weeks after the third time point. In some cases, the fourth dose comprises the
same amount of
anti-TL1A as the third dose. In some cases, the fourth dose comprises a
different amount of
anti-TL1A as the third dose. In some cases, the fourth dose comprises about
150 mg to about
700 mg, about 150 mg to about 300 mg, about 150 mg to about 225 mg, about 175
mg to
about 225 mg, about 400 mg to about 600 mg, about 450 mg to about 550 mg,
about 475 mg
to about 525 mg, or about 150 mg, about 160 mg, about 170 mg, about 180 mg,
about 190
mg, about 200 mg, about 210 mg, about 220, about 230 mg, about 240 mg, about
250 mg,
about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about
550 mg,
about 600 mg, about 650 mg, or about 700 mg anti-TL1A. In example embodiments,
the
fourth dose comprises about 175-300 mg anti-TL1A administered subcutaneously
about 1
week after the third dose. In example embodiments, the fourth dose comprises
about 500 mg
anti-TL1A administered intravenously about 2 weeks after the third dose.
1003781 In some embodiments, the method comprises administering to the subject
a fifth
dose of anti-TL1A at a fifth time point. In some cases, the fifth time point
is about 1, 2, 3, 4,
5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21,22, 23, 24,
25,26, 27,28, 29,30, or
31 days after the fourth time point. In some cases, the fifth time point is
about 1, 2, 3, or 4
weeks after the fourth time point. In some cases, the fifth dose comprises the
same amount of
anti-TL1A as the fourth dose. In some cases, the fifth dose comprises a
different amount of
anti-TL1A as the fourth dose. In some cases, the fifth dose comprises about
150 mg to about
700 mg, about 150 mg to about 300 mg, about 150 mg to about 225 mg, about 175
mg to
about 225 mg, about 400 mg to about 600 mg, about 450 mg to about 550 mg,
about 475 mg
to about 525 mg, or about 150 mg, about 160 mg, about 170 mg, about 180 mg,
about 190
mg, about 200 mg, about 210 mg, about 220, about 230 mg, about 240 mg, about
250 mg,
about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about
550 mg,
about 600 mg, about 650 mg, or about 700 mg anti-TL1A. In example embodiments,
the fifth
dose comprises about 175-300 mg anti-TL1A administered subcutaneously about 1
week
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after the fourth dose. In example embodiments, the fifth dose comprises about
500 mg anti-
TL1A administered intravenously about 2 weeks after the fourth dose.
1003791 In some embodiments, the method comprises administering to the subject
a sixth
dose of anti-TL1A at a sixth time point. In some cases, the sixth time point
is about 1, 2, 3, 4,
5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19,20, 21,22, 23,24, 25,26,
27,28, 29,30, or
31 days after the fifth time point. In some cases, the sixth time point is
about 1, 2, 3, or 4
weeks after the fifth time point. In some cases, the sixth dose comprises the
same amount of
anti-TLIA as the fifth dose. In some cases, the sixth dose comprises a
different amount of
anti-TL1A as the fifth dose. In some cases, the sixth dose comprises about 150
mg to about
700 mg, about 150 mg to about 300 mg, about 150 mg to about 225 mg, about 175
mg to
about 225 mg, about 400 mg to about 600 mg, about 450 mg to about 550 mg,
about 475 mg
to about 525 mg, or about 150 mg, about 160 mg, about 170 mg, about 180 mg,
about 190
mg, about 200 mg, about 210 mg, about 220, about 230 mg, about 240 mg, about
250 mg,
about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about
550 mg,
about 600 mg, about 650 mg, or about 700 mg anti-TL1A. In example embodiments,
the
sixth dose comprises about 1 75-3 00 mg anti-TL1A administered subcutaneously
about 1
week after the fifth dose. In example embodiments, the sixth dose comprises
about 500 mg
anti-TL1A administered intravenously about 2 weeks after the fifth dose.
1003801 In some embodiments, the method comprises administering to the subject
a
seventh dose of anti-TL1A at a seventh time point. In some cases, the seventh
time point is
about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15,16, 17,18, 19,20, 21,
22, 23,24,25,26,
27, 28, 29, 30, or 31 days after the sixth time point. In some cases, the
seventh time point is
about 1, 2, 3, or 4 weeks after the sixth time point. In some cases, the
seventh dose comprises
the same amount of anti-TL1A as the sixth dose. In some cases, the seventh
dose comprises a
different amount of anti-TLIA as the sixth dose. In some cases, the seventh
dose comprises
about 150 mg to about 700 mg, about 150 mg to about 300 mg, about 150 mg to
about 225
mg, about 175 mg to about 225 mg, about 400 mg to about 600 mg, about 450 mg
to about
550 mg, about 475 mg to about 525 mg, or about 150 mg, about 160 mg, about 170
mg, about
180 mg, about 190 mg, about 200 mg, about 210 mg, about 220, about 230 mg,
about 240
mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg,
about 500 mg
about 550 mg, about 600 mg, about 650 mg, or about 700 mg anti-TL1A. In
example
embodiments, the seventh dose comprises about 175-300 mg anti-TL1A
administered
subcutaneously about 1 week after the sixth dose. In example embodiments, the
seventh dose
comprises about 500 mg anti-TLIA administered intravenously about 2 weeks
after the sixth
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dose.
1003811 In some embodiments, the method comprises administering to the subject
an
eighth dose of anti-TLIA at an eighth time point. In some cases, the eighth
time point is
about I, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15,16, 17,18, 19,20, 21,
22, 23,24, 25, 26,
27, 28, 29, 30, or 31 days after the seventh time point. In some cases, the
eighth time point is
about 1, 2, 3, or 4 weeks after the seventh time point. In some cases, the
eighth dose
comprises the same amount of anti-TL1A as the seventh dose. In some cases, the
eighth dose
comprises a different amount of anti-TLIA as the seventh dose. In some cases,
the eighth
dose comprises about 150 mg to about 700 mg, about 150 mg to about 300 mg,
about 150 mg
to about 225 mg, about 175 mg to about 225 mg, about 400 mg to about 600 mg,
about 450
mg to about 550 mg, about 475 mg to about 525 mg, or about 150 mg, about 160
mg, about
170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220,
about 230
mg, about 240 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg,
about 450 mg
about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg anti-
TL1A. In
example embodiments, the eighth dose comprises about 175-300 mg anti-TL1A
administered
subcutaneously about 1 week after the seventh dose. In example embodiments,
the eighth
dose comprises about 500 mg anti-TLIA administered intravenously about 2 weeks
after the
seventh dose.
1003821 In some embodiments, the method comprises administering to the subject
a ninth
dose of anti-TLIA at a ninth time point. In some cases, the ninth time point
is about 1,2, 3,4,
5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23,24,
25,26, 27,28, 29,30, or
31 days after the eighth time point. In some cases, the ninth time point is
about 1, 2, 3, or 4
weeks after the eighth time point. In some cases, the ninth dose comprises the
same amount
of anti-TL1A as the eighth dose. In some cases, the ninth dose comprises a
different amount
of anti-TLIA as the eighth dose. In some cases, the ninth dose comprises about
150 mg to
about 700 mg, about 150 mg to about 300 mg, about 150 mg to about 225 mg,
about 175 mg
to about 225 mg, about 400 mg to about 600 mg, about 450 mg to about 550 mg,
about 475
mg to about 525 mg, or about 150 mg, about 160 mg, about 170 mg, about 180 mg,
about 190
mg, about 200 mg, about 210 mg, about 220, about 230 mg, about 240 mg, about
250 mg,
about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about
550 mg,
about 600 mg, about 650 mg, or about 700 mg anti-TL1A. In example embodiments,
the
ninth dose comprises about 175-300 mg anti-TLIA administered subcutaneously
about 1
week after the eighth dose. In example embodiments, the ninth dose comprises
about 500 mg
anti-TLIA administered intravenously about 2 weeks after the eighth dose.
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[00383] In some embodiments, the method comprises administering to the subject
a tenth
dose of anti-TL1A at a tenth time point. In some cases, the tenth time point
is about 1, 2, 3, 4,
5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19,20, 21,22, 23,24, 25,26,
27,28, 29, 30, or
31 days after the ninth time point. In some cases, the tenth time point is
about 1, 2, 3, or 4
weeks after the ninth time point. In some cases, the tenth dose comprises the
same amount of
anti-TL1A as the ninth dose. In some cases, the tenth dose comprises a
different amount of
anti-TL1A as the ninth dose. In some cases, the tenth dose comprises about 150
mg to about
700 mg, about 150 mg to about 300 mg, about 150 mg to about 225 mg, about 175
mg to
about 225 mg, about 400 mg to about 600 mg, about 450 mg to about 550 mg,
about 475 mg
to about 525 mg, or about 150 mg, about 160 mg, about 170 mg, about 180 mg,
about 190
mg, about 200 mg, about 210 mg, about 220, about 230 mg, about 240 mg, about
250 mg,
about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about
550 mg,
about 600 mg, about 650 mg, or about 700 mg anti-TL1A. In example embodiments,
the
tenth dose comprises about 175-300 mg anti-TL1A administered subcutaneously
about 1
week after the ninth dose. In example embodiments, the tenth dose comprises
about 500 mg
anti-TL1A administered intravenously about 2 weeks after the ninth dose.
[00384] In some embodiments, the method comprises administering to the subject
an
eleventh dose of anti-TL1A at an eleventh time point. In some cases, the
eleventh time point
is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20,
21, 22, 23, 24, 25,
26, 27, 28, 29, 30, or 31 days after the tenth time point. In some cases, the
eleventh time point
is about 1, 2, 3, or 4 weeks after the tenth time point. In some cases, the
eleventh dose
comprises the same amount of anti-TL1A as the tenth dose. In some cases, the
eleventh dose
comprises a different amount of anti-TL1A as the tenth dose. In some cases,
the eleventh
dose comprises about 150 mg to about 700 mg, about 150 mg to about 300 mg,
about 150 mg
to about 225 mg, about 175 mg to about 225 mg, about 400 mg to about 600 mg,
about 450
mg to about 550 mg, about 475 mg to about 525 mg, or about 150 mg, about 160
mg, about
170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220,
about 230
mg, about 240 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg,
about 450 mg,
about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg anti -
TL1A. In
example embodiments, the eleventh dose comprises about 175-300 mg anti-TL1A
administered subcutaneously about 1 week after the tenth dose. In example
embodiments, the
eleventh dose comprises about 500 mg anti-TL1A administered intravenously
about 2 weeks
after the tenth dose.
[00385] In some embodiments, the method comprises administering to the subject
a
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twelfth dose of anti-TL1A at a twelfth time point. In some cases, the twelfth
time point is
about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15,16, 17,18, 19,20, 21,
22, 23,24,25,26,
27, 28, 29, 30, or 31 days after the eleventh time point. In some cases, the
twelfth time point
is about 1, 2, 3, or 4 weeks after the eleventh time point. In some cases, the
twelfth dose
comprises the same amount of anti-TL1A as the eleventh dose. In some cases,
the twelfth
dose comprises a different amount of anti-TL1A as the eleventh dose. In some
cases, the
twelfth dose comprises about 150 mg to about 700 mg, about 150 mg to about 300
mg, about
150 mg to about 225 mg, about 175 mg to about 225 mg, about 400 mg to about
600 mg,
about 450 mg to about 550 mg, about 475 mg to about 525 mg, or about 150 mg,
about 160
mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg,
about 220,
about 230 mg, about 240 mg, about 250 mg, about 300 mg, about 350 mg, about
400 mg,
about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about
700 mg
anti-TL1A. In example embodiments, the twelfth dose comprises about 175-300 mg
anti-
TL1A administered subcutaneously about 1 week after the eleventh dose. In
example
embodiments, the twelfth dose comprises about 500 mg anti-TL1A administered
intravenously about 2 weeks after the eleventh dose.
[00386] In some embodiments, the method comprises administering to the subject
a
thirteenth dose of anti-TL1A at a thirteenth time point. In some cases, the
thirteenth time
point is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,
19, 20, 21, 22, 23, 24,
25, 26, 27, 28, 29, 30, or 31 days after the twelfth time point. In some
cases, the thirteenth
time point is about 1,2, 3, or 4 weeks after the twelfth time point. In some
cases, the
thirteenth dose comprises the same amount of anti-TL1A as the twelfth dose. In
some cases,
the thirteenth dose comprises a different amount of anti-TL1A as the twelfth
dose. In some
cases, the thirteenth dose comprises about 150 mg to about 700 mg, about 150
mg to about
300 mg, about 150 mg to about 225 mg, about 175 mg to about 225 mg, about 400
mg to
about 600 mg, about 450 mg to about 550 mg, about 475 mg to about 525 mg, or
about 150
mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg,
about 210 mg
about 220, about 230 mg, about 240 mg, about 250 mg, about 300 mg, about 350
mg, about
400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg,
or about
700 mg anti-TL1A. In example embodiments, the thirteenth dose comprises about
175-300
mg anti-TL1A administered subcutaneously about 1 week after the twelfth dose.
In example
embodiments, the thirteenth dose comprises about 500 mg anti-TL1A administered
intravenously about 2 weeks after the twelfth dose.
[00387] In some embodiments, the method comprises administering to the subject
a
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fourteenth dose of anti-TL1A at a fourteenth time point. In some cases, the
fourteenth time
point is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,
19, 20, 21, 22, 23, 24,
25, 26, 27, 28, 29, 30, or 31 days after the thirteenth time point. In some
cases, the fourteenth
time point is about 1,2, 3, or 4 weeks after the thirteenth time point. In
some cases, the
fourteenth dose comprises the same amount of anti-TL1A as the thirteenth dose.
In some
cases, the fourteenth dose comprises a different amount of anti-TL1A as the
thirteenth dose.
In some cases, the fourteenth dose comprises about 150 mg to about 700 mg,
about 150 mg to
about 300 mg, about 150 mg to about 225 mg, about 175 mg to about 225 mg,
about 400 mg
to about 600 mg, about 450 mg to about 550 mg, about 475 mg to about 525 mg,
or about
150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg,
about 210
mg, about 220, about 230 mg, about 240 mg, about 250 mg, about 300 mg, about
350 mg,
about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about
650 mg, or
about 700 mg anti-TL1A. In example embodiments, the fourteenth dose comprises
about
175-300 mg anti-TL1A administered subcutaneously about 1 week after the
thirteenth dose.
In example embodiments, the fourteenth dose comprises about 500 mg anti-TL1A
administered intravenously about 2 weeks after the thirteenth dose.
[00388] In some embodiments, the method comprises administering to the subject
a
fifteenth dose of anti-TL1A at a fifteenth time point. In some cases, the
fifteenth time point is
about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15,16, 17,18, 19,20, 21,
22, 23,24, 25,26,
27, 28, 29, 30, or 31 days after the fourteenth time point. In some cases, the
fifteenth time
point is about 1, 2, 3, or 4 weeks after the fourteenth time point. In some
cases, the fifteenth
dose comprises the same amount of anti-TL1A as the fourteenth dose. In some
cases, the
fifteenth dose comprises a different amount of anti-TL1A as the fourteenth
dose. In some
cases, the fifteenth dose comprises about 150 mg to about 700 mg, about 150 mg
to about
300 mg, about 150 mg to about 225 mg, about 175 mg to about 225 mg, about 400
mg to
about 600 mg, about 450 mg to about 550 mg, about 475 mg to about 525 mg, or
about 150
mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg,
about 210 mg
about 220, about 230 mg, about 240 mg, about 250 mg, about 300 mg, about 350
mg, about
400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg,
or about
700 mg anti-TL1A. In example embodiments, the fifteenth dose comprises about
175-300 mg
anti-TL1A administered subcutaneously about 1 week after the fourteenth dose.
In example
embodiments, the fifteenth dose comprises about 500 mg anti-TL1A administered
intravenously about 2 weeks after the fourteenth dose.
[00389] In some embodiments where the subject is responsive to treatment, the
subject is
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further treated with anti-TL1A in a maintenance phase. As a non-limiting
example, treatment
comprises 1 to about 20 doses, 1 to about 12 doses, 1 to about 6 doses, about
6 doses or about
12 doses. In some embodiments, the maintenance phase comprises administration
of about
150 mg to about 250 mg, about 150 mg to about 225 mg, about 150 mg to about
200 mg,
about 175 mg to about 225 mg, about 175 to about 200 mg, about 150 mg, about
160 mg,
about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about
220, about
230 mg, about 240 mg, or about 250 mg anti-TL1A in one or more doses. In some
cases,
maintenance comprises administration of a dose of anti-TL1A every 1, 2, 3, or
4 weeks. In
some cases, maintenance comprises administration of a dose of about 175 mg to
about 300
mg every 2 weeks. In some cases, maintenance comprises administration of a
dose of about
175 mg to about 300 mg every 4 weeks. In some cases, the administration is
subcutaneous. In
some cases, the administration is intravenous.
1003901 In one aspect, a method of treatment comprises administrating to the
subject a first
dose on day 0, a second dose on day 7, a third dose on day 14, a fourth dose
on day 21, a fifth
dose on day 28, a sixth dose on day 35, a seventh dose on day 42, an eighth
dose on day 49, a
ninth dose on day 56, a tenth dose on day 63, an eleventh dose on day 70, a
twelfth dose on
day 77, and optionally a thirteenth dose is administered on day 84. In some
embodiments, the
first dose comprises about 500-1000 mg or about 800 mg anti-TL1A. In some
embodiments,
the second dose comprises about 175-300 mg anti-TL1A. In some embodiments, the
third
dose comprises about 175-300 mg anti-TL1A. In some embodiments, the fourth
dose
comprises about 175-300 mg anti-TL1A. In some embodiments, the fifth dose
comprises
about 175-300 mg anti-TL1A. In some embodiments, the sixth dose comprises
about 175 -300
mg anti-TL1A. In some embodiments, the seventh dose comprises about 175-300 mg
anti-
ml A. In some embodiments, the eighth dose comprises about 175-300 mg anti-TL1
A. In
some embodiments, the ninth dose comprises about 175-300 mg anti-TL1A. In some
embodiments, the tenth dose comprises about 175-300 mg anti-TL1A. In some
embodiments,
the eleventh dose comprises about 175-300 mg anti-TL1A. In some embodiments,
the twelfth
dose comprises about 175-300 mg anti-TL1A. In some embodiments, the thirteenth
dose
comprises about 175-300 mg anti-TL1A. The anti-TL1A may be administered
subcutaneously, e.g., in a composition disclosed herein. In some embodiments
where the
subject is responsive to treatment, the subject is further treated with anti-
TL1A in a
maintenance phase. In some cases, maintenance comprises administration of a
dose of about
175 mg to about 300 mg every 2 weeks. In some cases, maintenance comprises
administration of a dose of about 175 mg to about 300 mg every 4 weeks. In
some cases, the
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maintenance administration is subcutaneous. In some cases, the maintenance
administration
is intravenous. In a non-limiting embodiment, the first dose is an i.v. dose,
and one or more
subsequent doses is a s.c. dose. For instance, in some cases, the induction
period comprises
i.v. administration and the maintenance period comprises s.c. administration.
1003911 In one aspect, a method of treatment comprises administrating to the
subject a first
dose on day 0, a second dose on day 14, a third dose on day 28, a fourth dose
on day 42, a
fifth dose on day 56, a sixth dose on day 70, and optionally a seventh dose on
day 84. In
some embodiments, the first dose comprises about 400-600 mg or about 500 mg
anti-TL1A.
In some embodiments, the second dose comprises about 400-600 mg anti-TL II A.
In some
embodiments, the third dose comprises about 400-600 mg anti-TL1A. In some
embodiments,
the fourth dose comprises about 400-600 mg anti-TL1A. In some embodiments, the
fifth dose
comprises about 400-600 mg anti-TL1A. In some embodiments, the sixth dose
comprises
about 400-600 mg anti-TL1A. In some embodiments, the seventh dose comprises
about 400-
600 mg anti-TL1A. The anti-TL1A may be administered intravenously, e.g., by
diluting a
composition herein to a suitable volume for administration, such as about 250
mL. In some
cases, maintenance comprises administration of a dose of about 175 mg to about
300 mg
every 2 weeks. In some cases, maintenance comprises administration of a dose
of about 175
mg to about 300 mg every 4 weeks. In some cases, the maintenance
administration is
subcutaneous. In some cases, the maintenance administration is intravenous. In
a non-limiting
embodiment, the first dose is an i.v. dose, and one or more subsequent doses
is a s.c. dose.
For instance, in some cases, the induction period comprises i.v.
administration and the
maintenance period comprises s.c. administration.
5. EXAMPLES
1003921 The following examples are illustrative of the embodiments described
herein and
are not to be interpreted as limiting the scope of this disclosure. To the
extent that specific
materials are mentioned, it is merely for purposes of illustration and is not
intended to be
limiting. One skilled in the art may develop equivalent means or reactants
without the
exercise of inventive capacity and without departing from the scope of this
disclosure.
Example 1: Design of humanized anti-TL1A antibodies
1003931 Two different strategies were employed to identify humanized variants
that
express well in mammalian cells, preserve TL1A binding, and display high
monomeric
content.
1003941 The first strategy utilized a previously humanized variant, termed
ASX, that
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displays high monomeric content (98%) and expresses well (30 ug/mL in small-
scale
transient cultures) as a template for additional mutagenesis. However, ASX
contains a
significant number of murine framework residues, eight heavy chain residues
and 7 light
chain residues, that may pose an immunogenicity risk. The ASX heavy and light
chain
templates were used to systematically mutate murine framework residues to
human residues
corresponding to the most closely related human germline framework. The goal
of this
strategy was to reduce the total number of murine framework residues while
preserving the
favorable expression and solubility characteristics of ASX. Because ASX
contained 15
murine framework residues there were 2^15 (32,768) distinct variants
(restricting each
position to either the murine or the human residue) that could be made and
tested.
[00395] The second strategy utilized a previously humanized variant, termed
c34, that
expresses well (17 ug/mL in small-scale transient cultures) and contains CDRs
optimized for
binding within a fully human germline framework, as a template for additional
mutagenesis.
Large-scale expression of c34 unexpectedly resulted in a sub -optimal
monomeric content
(55-60%). The c34 heavy and light chain templates were used to systematically
mutate
certain framework residues to murine residues corresponding to the original
murine antibody
framework. The goal of this strategy was to improve the solubility of c34
(monomeric
content) through the introduction of as few murine framework residues as
possible
(minimizing potential immunogenicity risks) while preserving the favorable
expression
characteristics of c34.
[00396] For both strategies, the initial approach was to scan differing
framework residues,
one at a time, and express and characterize the variants. Thus, human
framework residues
were introduced into variant ASX where it differed from c34 and conversely,
murine
framework mutations were introduced into variant c34 where it differed from A
SX. The
initial scan identified certain framework and CDR residues that had minimal
impact on the
characteristics displayed by the template antibody while other mutations had a
more dramatic
impact, favorable in some cases and unfavorable in others. The information
gained from the
positional scan was subsequently used in an iterative and combinatorial
fashion, to identify
multiple variants with favorable characteristics. Importantly, by applying a
stepwise, iterative
and combinatorial approach the beneficial variants were identified without
necessitating the
expression and characterization of 32,768 distinct variants.
[00397] In certain cases, mutation of the first residue of the heavy chain
from glutamine to
aspartic acid or glutamic acid was evaluated, alone or in combination with
other mutations.
[00398] In addition, for both strategies certain CDR residues were also
mutated to
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determine the impact on expression and solubility. For example, a limited
number of
mutations in HCDR2, HCDR3 and LCDR3 were examined. Similar to the approach
used
with frameworks, the mutations were predominantly restricted to the original
murine CDR
residue or mutations that were previously identified as enhancing binding
affinity.
1003991 Finally, for both strategies "shuffling" of heavy and light chains was
used.
Specifically, certain human light chains containing few murine framework
residues and
having a favorable impact on expression of antibody with higher monomeric
content were
identified early in the process and these were paired with various engineered
heavy chains in
order to accelerate the process of identifying suitable variants.
1004001 Examples of certain designed antibodies are shown in Table 1.
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Table 1. Variable region sequences of select anti-TL1A Antibodies
Antibody Heavy Chain Variable Region Light Chain Variable
Region
SEQ 1D NO SEQ 1D NOS
A15 108 203
A29 108 205
A30 108 204
A31 136 205
A32 137 205
A33 137 202
A34 107 208
A35 138 208
A36 139 208
A37 140 208
A38 141 208
A39 142 208
A40 143 208
A41 115 208
A42 144 208
A43 145 208
A44 146 208
A45 120 208
A46 147 208
A47 148 208
A48 108 210
A49 108 211
A50 108 212
A51 108 213
A52 108 214
A53 146 208
A54 149 208
ASS 109 208
A56 108 215
A57 150 202
A58 125 202
A59 117 202
A60 151 202
A61 152 202
A62 153 202
A63 154 202
A64 121 202
A65 128 202
A66 155 202
A67 122 202
A68 123 202
A69 156 202
A70 157 202
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A71 158 202
A72 131 202
A73 157 205
A74 158 205
A75 131 205
A76 159 202
A77 160 202
A78 124 202
A79 107 208
A81 139 208
A82 140 208
A83 144 208
A85 136 209
A86 136 216
A87 136 217
A88 136 218
A89 136 219
A90 136 220
A91 133 202
A92 161 202
A93 162 202
A94 124 202
A95 131 205
A96 128 205
A97 121 202
A98 122 202
A99 123 202
A100 107 204
A101 140 204
A102 115 204
A103 120 204
A104 139 204
A105 143 204
A107 108 202
A108 156 205
A109 133 205
A110 125 205
A111 150 205
A112 117 205
A113 124 205
A114 121 205
A115 122 205
A116 123 205
A117 151 205
A118 153 205
A119 159 205
A120 154 205
A121 163 204
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A122 113 204
A123 112 204
A124 164 204
A125 105 204
A126 114 204
A127 118 204
A128 111 204
A129 110 204
A130 121 205
A132 128 206
A133 121 206
A134 122 206
A135 133 206
A136 125 206
A137 121 207
A138 122 207
A139 110 207
A140 110 202
A141 111 207
A142 111 202
A143 136 202
A144 111 204
A145 133 201
A146 125 201
A147 117 201
A148 121 201
A149 122 201
A150 128 201
A151 124 201
A152 131 201
A153 133 205
A154 125 205
A155 121 205
A156 122 205
A157 104 204
A158 101 204
A159 119 204
A160 102 204
A161 165 204
A162 106 204
A163 166 204
A164 167 204
A165 139 205
A166 146 205
A167 120 205
A168 147 205
A169 126 205
A170 135 205
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A171 168 205
A172 130 205
A173 127 205
A174 132 205
A175 126 201
A176 135 201
A177 168 201
A178 130 201
A179 127 201
A180 132 201
A181 107 202
A182 138 202
A183 140 202
A184 145 202
A185 147 202
A186 144 202
A187 120 202
A188 115 202
A189 146 202
A190 141 202
A191 142 202
A192 143 202
A193 109 205
A194 103 205
A195 169 205
A196 129 205
A197 116 205
A198 134 205
A199 109 201
A200 103 201
A201 169 201
A202 129 201
A203 116 201
A204 134 201
A205 109 202
A206 103 202
A207 169 202
A208 129 202
A209 116 202
A210 134 202
A211 108 201
A212 107 201
A213 106 201
A214 111 201
A215 110 201
A216 112 201
A217 101 201
A218 119 201
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A219 104 201
A220 102 205
A221 105 201
A222 114 201
A223 103 202
A224 116 201
A500 301 303
A501 302 303
[00401] As used herein, reference to A(number), refers to an antibody of this
table. For
instance, Al5 used herein refers to Al 5 in Table 1.
Example 2: Generation and characterization of humanized anti-TL1A antibodies
[00402] Humanized anti-TL1A antibodies designed in Example 1 were prepared and
characterized.
[00403] Cloning of humanized antibodies
[00404] DNA encoding leader sequence and the heavy and light chain variable
regions of
humanized variants of interest was cloned into pFusel-hIgGl-Fcl (InvivoGen)
and pFuse2-
CLig-hk (InvivoGen), respectively. Two distinct humanized heavy chain
templates, termed
ASX-HC and c34-HC, and four distinct humanized light chain templates, termed
ASX-LC,
cH3-1, c34-LC, cXL3-13-LC and cXL3-15-LC were all cloned.
[00405] In order to introduce mutations into the templates, the QuickChange
Site Directed
Mutagenesis Kit (Agilent, cat. #200518) was used per manufacturer's
directions. Briefly,
mutagenesis was performed using miniprep double-stranded plasmid DNA, two
synthetic
oligonucleotides primers containing the desired mutation, PfuTurbog DNA
polymerase and a
temperature cycler. Following temperature cycling, the product was treated
with Dpn I. The
nicked vector DNA containing the mutation(s) of interest was used to transform
bacteria.
Subsequently, colonies were picked, the DNA was sequenced to confirm
mutagenesis and
was subsequently used for transfection of mammalian FreeStyle 293 -F cells.
[00406] Antibody expression
[00407] Small-scale (3 mL, 6-well) expression of variants in Free
Style 293-F cells was
performed in the following manner One or two days prior to transfection cells
were passaged
so that the density would be >1 x 106 cells/mL on the day of the transfection.
Typically, this
meant passaging at 6-7 x 105 cells/mL one day prior or 4 x 105 cells/mL two
days prior.
Transfections were only performed with cell viability >90%. On the day of the
transfection
Opti-MEM media was warmed to 37 C and cells were resuspended to 1.1 x 106
cells/mL,
using 3.3 x 106 cells per 3 mL transfection. A total of 3 pig DNA was used for
each
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transfection. Briefly, the transfections used heavy and light chain plasmid at
a heavy
chain:light chain ratio of 1:3. For 3 mL transfections, 4 pi,L, 293fectin was
added to 96 [IL
Opti-MEM, combined with 100 H.1_, DNA mixture, and incubated at 25 C for 20-30
minutes.
Subsequently, this mixture was added dropwise to 2.8 InL cells and the plate
was transferred
to an incubator and placed on a rotating platform at 175 rpm for up to 120
hours. After 96-
120 hours, transfection supernatants were collected by centrifuging the
transfected cells and
supernatant at 1200 rpm for 5 mm. The supernatant was transferred to a clean
tube and
centrifuged again at 3900 rpm for 10 min to remove any remaining cell debris.
The
supernatant was filtered through a 0.45 mm PES syringe filter and stored at 4
C until the next
step.
1004081 Quantitation of antibody expression
[00409] Antibody expression was quantitated by ELISA. Briefly, a Corning
Costar 3366
96-well round bottom high bind plate was coated with 50 mL anti-kappa (2
[tg/mL) in PBS
overnight at 4 C. The plate was washed 3x with PBS-0.05% Tween 20 (PBS-T) and
was
blocked with 100 [IL 1% BSA/PBS for 1 h at 25 C The block was removed, and
culture
supernatant diluted 5-fold was added and serially diluted 2-fold across the
plate. Every plate
also contained an IgG standard diluted serially 3-fold beginning at 1 gg/mL.
Samples were
incubated for 1 h at 25 C, the plate was washed three times with PBS-T, and 50
anti-Fc
HRP secondary (Southern Biotech #2048-05), diluted 1:4000 in BSA/PBS was added
for 1 h
at 25 C. The plate was washed three times with PBS-T and developed for up to
15 min
following the addition of 501AL Ultra TMB ELISA substrate (Thermo #34028). The
reaction
was terminated by the addition of 50 [it 2 N H2504 and the A450 nm was
measured.
Antibody expression levels obtained from 3 mL scale transfections are shown in
Table 2.
Table 2. Expression, binding, and analytical SEC characterization of anti-TL1A
antibodies
(ND, not determined)
Expression KD Murine HC LC
Variant
(g/mL) (PM) Monomer FR Template
Template
15 21 ND 87 8 ASX
cH3-1
29 18 65 65 10 ASX
c34
30 29 77 90 8 ASX
cXL3-13
31 11 92 73 2 c34
c34
32 10 111 78 2+D c34
c34
33 21 81 54 0+D c34
c34
34 35 <50 97 14 ASX
ASX
35 36 72 91 14 ASX
ASX
36 40 <50 87 13 ASX
ASX
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Expression KD % Murine HC LC
Variant
(it g/mL) (pM) Monomer FR
Template Template
37 40 34 95 14 ASX
ASX
38 28 103 75 14 ASX
ASX
39 15 125 83 14 ASX
ASX
40 30 <50 87 13 ASX
ASX
41 20 16 96 14 ASX
ASX
42 30 <50 88 14 ASX
ASX
43 18 51 90 14 ASX
ASX
44 ND ND ND 13 ASX
ASX
45 15 85 90 13 ASX
ASX
46 27 63 72 13 ASX
ASX
47 18 82 78 12 ASX
ASX
48 22 76 92 14 ASX
ASX
49 26 92 65 13 ASX
ASX
50 33 19 94 14 ASX
ASX
51 16 <50 93 14 ASX
ASX
52 29 27 91 13 ASX
ASX
53 26 126 84 13 ASX
ASX
54 25 83 94 15+D ASX
ASX
55 22 91 99 15+E ASX
ASX
56 15 116 71 14 ASX
ASX
57 20 191 59 1 c34
c34
58 9 112 67 1 c34
c34
59 11 136 78 2 c34
c34
60 19 168 57 0 c34
c34
61 15 127 44 1 c34
c34
62 21 150 58 1 c34
c34
63 20 132 52 0 c34
c34
64 2 90 97 0 c34
c34
65 7 97 69 1 c34
c34
66 19 150 49 1 c34
c34
67 4 89 97 1 c34
c34
68 2 74 92 1 c34
c34
69 12 136 64 0+E c34
c34
70 15 149 54 1 c34
c34
71 18 150 55 2 c34
c34
72 13 159 61 3 c34
c34
73 8 128 71 3 c34
c34
74 10 141 70 4 c34
c34
75 8 259 95 5 c34
c34
76 19 ND 50 0 c34
c34
77 12 ND 50 2 c34
c34
78 3 ND 86 7 c34
c34
79 42 ND 98 14 ASX
ASX
81 31 ND 88 13 ASX
ASX
82 26 ND 92 14 ASX
ASX
83 29 ND 74 14 ASX
ASX
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Expression KD % Murine HC LC
Variant
(it g/mL) (pM) Monomer FR
Template Template
85 25 130 49 1 c34
c34
86 26 129 55 1 c34
c34
87 26 121 52 1 c34
c34
88 9 81 63 2 c34
c34
89 31 117 55 1 c34
c34
90 19 107 53 1 c34
c34
91 14 132 63 1 c34
c34
92 20 121 49 1 c34
c34
93 12 117 63 2 c34
c34
94 5 81 91 2 c34
c34
95 13 105 92 5 c34
c34
96 7 95 99 3 c34
c34
97 2 71 97 0 c34
c34
98 7 140 98 1 c34
c34
99 3 102 95 1 c34
c34
100 39 84 84 7 ASX
cXL3-13
101 23 96 81 7 ASX
cXL3-13
102 19 104 75 7 ASX
cXL3-13
103 11 107 90 6 ASX
cXL3-13
104 26 108 70 6 ASX
cXL3 -13
105 23 110 58 6 ASX
cXL3-13
107 55 71 85 8 ASX
c34
108 9 55 83 2+E c34
c34
109 9 50 96 3 c34
c34
110 7 56 95 3 c34
c34
111 17 68 61 3 c34
c34
112 6 54 93 4 c34
c34
113 2 50 99 4 c34
c34
114 1 51 99 2 c34
c34
115 3 58 99 3 c34
c34
116 1 53 99 3 c34
c34
117 16 94 80 2 c34
c34
118 21 83 70 3 c34
c34
119 15 87 77 2 c34
c34
120 12 85 64 2 c34
c34
121 24 106 77 6 ASX
cXL3-13
122 22 112 85 6 ASX
cXL3-13
123 18 104 76 5 ASX
cXL3-13
124 21 91 83 6 ASX
cXL3-13
125 10 116 98 6 ASX
cXL3 -13
126 4 123 99 5 ASX
cXL3-13
127 8 70 94 6 ASX
cXL3-13
128 17 111 84 4 ASX
cXL3-13
129 17 99 92 5 ASX
cXL3-13
130 1 75 99 2 c34
c34
132 6 62 99 2 c34
cXL3-13
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Expression KD % Murine HC LC
Variant
(it g/mL) (pM) Monomer FR
Template Template
133 1 58 99 1 c34
cXL3-13
134 3 55 99 2 c34
cXL3-13
135 7 56 74 2 c34
cXL3-13
136 6 53 84 2 c34
cXL3-13
137 2 50 96 0 c34
cXL3 -15
138 5 69 99 1 c34
cXL3 -15
139 35 74 78 5 ASX
cXL3-15
140 26 73 75 5 ASX
c34
141 27 108 81 4 ASX
cXL3-15
142 25 126 68 4 ASX
c34
143 16 85 57 0 c34
c34
144 ND ND ND 4 ASX
cXL3 -13
145 20 70 78 2 c34
c34
146 25 65 84 2 c34
c34
147 26 63 87 3 c34
c34
148 2 46 98 1 c34
c34
149 7 48 99 2 c34
c34
150 15 59 83 2 c34
c34
151 5 57 96 3 c34
c34
152 36 58 73 4 c34
c34
153 9 49 97 3 c34
c34
154 8 66 92 3 c34
c34
155 1 67 99 2 c34
c34
156 2 94 99 3 c34
c34
157 6 69 93 4 ASX
cXL3 -13
158 6 66 91 3 ASX
cXL3-13
159 4 69 99 4 ASX
cXL3-13
160 7 94 99 4 ASX
cXL3-13
161 11 72 59 4 ASX
cXL3-13
162 9 75 79 3 ASX
cXL3 -13
163 22 51 60 4 ASX
cXL3-13
164 23 58 61 4 ASX
cXL3-13
165 19 59 53 8 ASX
c34
166 13 57 76 8 ASX
c34
167 9 42 96 8 ASX
c34
168 16 62 85 8 ASX
c34
169 8 47 90 3 c34
c34
170 9 49 93 3 c34
c34
171 13 50 80 5 c34
c34
172 7 40 96 3 c34
c34
173 4 40 99 4 c34
c34
174 4 43 98 4 c34
c34
175 31 45 86 2 c34
c34
176 18 48 80 2 c34
c34
177 35 52 67 4 c34
c34
178 18 43 85 2 c34
c34
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Expression KD
% Murine HC LC
Variant
(it g/mL) (pM) Monomer FR
Template Template
179 16 79 93 3 c34 c34
180 17 58 94 3 c34 c34
181 46 60 87 7 ASX c34
182 39 67 74 7 ASX c34
183 38 65 82 7 ASX c34
184 30 61 73 7 ASX c34
185 30 56 66 6 ASX c34
186 38 67 66 7 ASX c34
187 27 56 72 6 ASX c34
188 31 63 87 7 ASX c34
189 44 76 71 6 ASX c34
190 32 57 69 7 ASX c34
191 21 57 80 7 ASX c34
192 27 55 70 6 ASX c34
193 16 55 68 10+E ASX c34
194 16 51 87 9 +E ASX c34
195 12 56 82 5+E c34 c34
196 7 54 97 3+E c34 c34
197 7 54 97 3--E c34 c34
198 9 53 95 3+E c34 c34
199 28 50 93 9+E ASX c34
200 24 52 99 8+E ASX c34
201 25 58 82 4+E c34 c34
202 13 59 87 2+E c34 c34
203 18 62 89 2+E c34 c34
204 11 53 84 2+E c34 c34
205 27 55 86 8-}-E ASX c34
206 20 50 98 7 +E ASX c34
207 ND ND ND 3+E c34 c34
208 ND ND ND 1 +E c34 c34
209 14 58 66 1+E c34 c34
210 15 70 61 1+E c34 c34
211 42 58 96 9 ASX c34
212 33 50 99 8 ASX c34
213 29 49 99 4 ASX c34
214 27 51 97 5 ASX c34
215 20 48 77 6 ASX c34
216 24 49 97 6 ASX c34
217 15 43 99 4 ASX c34
218 13 51 96 5 ASX c34
219 21 50 99 5 ASX c34
770 18 50 99 6 ASX c34
221 23 51 98 7 ASX c34
222 29 60 96 6 ASX c34
223 19 62 98 7-FE ASX c34
224 15 76 92 2-FE c34 c34
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[00410] Antibody binding to human TL1A
[00411] Antibody binding to human TL1A (Fitzgerald #30R-AT070) was quantitated
by
ELISA. Briefly, a Corning Costar 3366 96-well round bottom high bind plate was
coated
with 50 !AL TL1A (1 mg/mL) in PBS overnight at 4 C. The plate was washed 3x
with PBS-
0.05% Tween 20 (PBS-T) and was blocked with 100 tL 1% BSA/PBS for 1 hat 25 C.
The
block was removed, and culture supernatant diluted 5-fold was added and
serially diluted 2 -
fold across the plate. Samples were incubated for 1 h at 25 C, the plate was
washed three
times with PBS-T, and 50 tL anti-Fc 1-1RP secondary, diluted 1:4000 in BSA/PBS
was added
for 1 h at 25 C. The plate was washed three times with PBS-T and developed for
up to 15
min following the addition of 50 jut Ultra TMEI ELISA substrate. The reaction
was
terminated by the addition of 50 [iL 2 N H2SO4 and the A450 nm was measured.
The
antibody affinities, as determined by ELISA titration against human TL1A using
unpurified
culture supernatants, is shown in Table 2.
[00412] Purification of antibodies
[00413] Antibodies were purified from culture supernatants in a single step
using
Dynabeads Protein A (ThermoFisher Scientific, cat. #10002D). First, culture
supernatants
were concentrated per manufacturer's instructions using an Amicon Ultra-4
Centrifugal Filter
Unit (30,000 MWCO; MilliporeSigma, cat. #C7719). The Dynabeads were
resuspended by
gentle vortexing and 100 viL were transferred to an Eppendorf tube. Using a
magnet to retain
the beads, the storage buffer was removed, and the beads were washed with 0.5
mL of 20
mM sodium phosphate, 150 mMNaC1, pH 7.4 (EB, Equilibration Buffer). A total of
up to 24
1.1,g of IgG from culture supernatant was added to the beads and mixed gently
until the beads
were resuspended. When necessary, antibody supernatants were diluted with EB.
The tubes
were placed sideways on a shaking platform and mixed for 10 min at 25 C at 500
rpm.
Subsequently, the beads were collected at the bottom of the tube using a
microfuge at 10,000
rpm for 30 sec. Using a magnet to retain the beads, the supernatant was
removed. The beads
were washed once with 0.5 mL of 20 mM sodium phosphate, 500 mM NaCl, pH 7.4
followed
by another wash with 50 mM sodium phosphate, pH 6Ø The beads were collected
at the
bottom of the tube using a microfuge at 10,000 rpm for 30 sec. Purified
antibody was eluted
from the beads using 20 1.11_, 50 mM sodium acetate, pH 3.5 with gentle mixing
for 2 min at
25 C. Using a magnet to retain the beads, the eluate was transferred to a
fresh tube containing
1.1 lit 1 M Tris, pH 8.5 to neutralize the pH of the sample. This sample was
then centrifuged
at 10,000 rpm for 2 min and transferred to a fresh tube to ensure removal of
residual
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Dynabeads. The concentration of the purified sample was determined using a
DeNovix DS-
11 Spectrophotometer/Fluorometer, buffer blank, and a mass extinction
coefficient of 13.70
at 280 nm for a 1% IgG solution.
1004141 Size exclusion chromatography
1004151 The antibodies were analyzed by size exclusion chromatography (SEC) to
determine percent monomer and identify any large molecular weight aggregate
contaminant
species. A total volume of 15 L of protein A purified antibodies at a
concentration of 0.1¨ 1
p,g/iaL were analyzed using a Waters SEC column (Acquity UPLC BEH SEC, 200 A,
1.7 pm,
4.6 x 150 mm) on a Shimadzu UPLC instrument at a flow rate of 0.2 mL/min and a
column
oven temperature of 30 C. Standard PBS was used as the mobile phase and
absorbance at
280 nm was used to monitor protein elution. For some antibody clones tested
that
demonstrated non-symmetrical elution profiles, PBS buffer supplemented with
350 mMNaC1
at pH 6.0 was utilized to reduced non-specific interactions with the column
matrix. The
percent main peak (monomer) value was calculated using the Shimadzu software.
Representative sample profiles are shown in FIGS. IA-C. The monomeric content
of purified
antibody variants is shown in Table 2.
Example 3: Design of humanized anti-TL1A antibodies with reduced effector
function
1004161 In certain cases, it might be beneficial to reduce the
potential effector function of
the antibodies. Multiple strategies to diminish effector function have been
described,
including point mutations to ablate FcyR and Clq binding, cross-subclass Fc
designs to
eliminate FcyR and Clq binding, and glycoengineering to ablate FcyR and Clq
binding.
Representative examples are highlighted in Table 3.
Table 3. Representative approaches to abrogating effector function
Mutation(s) Effect
E233P Decreases binding to FcyRI, II,
III
S228P, L235E SPLE in IgG4 Decreases binding to FcyRI
L235E Decreases binding to FcyRs
L234A, L235A Decreases binding to FcyRI, II,
III
L234A, L235A, G237A Decreases binding to FcyRI, II,
III, Clq
L234A, L235A, P329G Decreases binding to FcyRI, TI,
III, Clq
L234F, L235E, P331 S Decreases binding to FcyRI, TI,
III, CI q
L234A, L235E, G237A Decreases binding to FcyRI, II,
III, Clq
L234A, L235E, G237A, P331S Decreases binding to FcyRI, II,
III, Clq
L234A, L235A, G237A, P238S, H268A, Decreases binding to FcyRI, Ha,
IIb, Ma
A330S, P331S (IgGlo)
L234A, L235A, P329A Decreases binding to FcyRI, TI,
III, Clq
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G236R, L328R Decreases binding to FcyRI, II,
III
G237A Decreases binding to FcyRIT
F241A Decreases binding to Clq
V264A Decreases binding to Clq
D265A Decreases binding to FcyRI, TT,
TTT
D265A, N297A Decreases binding to FcyRI, II,
III, Clq
D265A, N297G Decreases binding to FcyRI, II,
III, Clq
D270A Decreases binding to Cl q
N297A, G, D, Q Elimination of N-linked
glycosylation
Decreases binding to FcyRI, II, III, Clq
P329A, G, R Decreases binding to Clq
A330L Decreases binding to Clq
P331A, S Diminished Clq binding
IgG2 Decreases binding to FcyRs
IgG4 Decreases binding to FcyRs;
Does not activate complement system
S228P Prevent IgG4 Fab arm exchange
S228P, F234A, L235A (IgG4) Decreases binding to FcyRI, Ha,
Ma
IgG2-IgG4 cross-subclass (IgG2/G4) Decreases binding to FcyRI, Ti,
ITT, Clq
IgG2-IgG3 cross-subclass Decreases binding to FcyRs;
Decreases binding to Clq
H268Q, V309L, A330S, P331S (Ig-G2m4) Decreases binding to FcyRI, TT, ITT, Cl q
V234 A, G237A, P238S, H268A, V309L, Decreases binding to FcyRI, Ha,
lib, Ma, Clq
A3305, P33 1S (IgG2 a)
High mannose glycosylation Decreases binding to Clq
[00417] In order to express antibodies with abrogated effector function, the
light chain
variable regions of the antibodies disclosed in Example 2 and Table 1 are
cloned with a
kappa light chain constant region, while the heavy chain variable regions are
cloned with a
modified IgG1 heavy chain backbone, or a modified IgG2 backbone, or a modified
IgG4
backbone, or an unmodified IgG2 or IgG4 backbone, such as those disclosed in
Table 3,
Table 13, Table 9B, or elsewhere.
[00418] The impact of the various Fc engineering approaches on CDC activity
can be
assessed using Clq binding and C3 fixation assays. Purified antibodies are
diluted in PBS
and serial dilutions are plated on a microtiter plate for 12-18h at 4 C. The
plates are blocked
with 5% gelatin/PBS containing 1% (v/v) Tween-20 for lh at 25 C. Subsequently,
the plates
are incubated with 10% (v/v) human sera in PBS and Clq binding is detected
using 1:500
dilution of HRP-conjugated rabbit anti-Clq (Bioss Inc.) in PBS containing 1%
(v/v) Tween-
20. To test C3 fixation, a 1:1000 dilution of rabbit anti C3 (abeam) is used
followed by a
1:2000 dilution of HRP-conjugated chicken anti-rabbit IgG (abeam). The plates
are
developed as described for antibody quantitation assays in Example 1. EC50
values are
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calculated by fitting the data to a log (agonist) vs. response-variable slope
(four parameter)
model using GraphPad Prism (Sunnyvale, CA).
[00419] Additionally, the variants may be characterized for the binding of
isolated Clq.
MaxiSorp 384-well plates (Thermo Scientific, Nunc) are coated with serially
diluted
antibodies in 50 mM carbonate buffer, pH 9.6 (coat buffer), for 12-18h at 4 C.
Plates are
washed with phosphate buffered saline (PBS) containing 0.05% polysorb ate 20,
pH 7.4 and
blocked with PBS containing 0.5% BSA, 0.05% polysorb ate 20, 15 ppm Proclin
and 10%
Blocker Casein (Thermo Scientific), pH 7.4. After 1-hour incubation at 25 C,
plates are
washed. Human Clq (Quidel, San Diego, CA) in the same buffer is added and
incubated for
1.5 hour. Bound Clq is detected by adding 20 ng/mL biotinylated mouse anti-
mouse Clq
(Hycult biotech; cross reacting with human Clq) for 1.5 hour followed by
horseradish
peroxidase (HRP)-conjugated streptavidin (GE Healthcare Life Sciences) for 1
hour. To
check for coating efficiency, some coated wells receive buffer only for the
first two
incubation steps and receive goat anti-human Fab'2-HRP when the wells used for
measuring
Clq binding received streptavidin-HRP. Plates are washed after each incubation
step.
Peroxidase activity is detected with substrate 3,3', 5, 5'-tetram ethyl b enzi
din e (TMB)
(Kirkegaard & Perry Laboratories). The reaction is stopped with 1M phosphoric
acid and
absorbance is measured at 450 nm. Dose-response binding curves are fitted with
a four-
parameter model and EC50 values are calculated using GraphPad Prism
(Sunnyvale, CA).
[00420] The impact of the various Fc engineering approaches on ADCC activity
is
assessed using soluble FcyR receptor binding ELISAs. Soluble human FcyRI,
FcyRII13 and
FcyRIII (binding affinity to both the F158 and V158 polymorphic forms of
FcyRIII is
assessed) are expressed as recombinant fusion proteins with Gly-His6-
glutathione-S-
transferase (GST) at the C-terminus of the extracellular domain of the
receptor. MaxiSorp
384-well plates are coated with 1 g/ml human FcyR in coat buffer. Plates are
washed and
blocked with PBS containing 0.5% BSA, 15 ppm Proclin, pH 7.4. After a 1 h
incubation,
plates are washed and 3-fold serial dilution of antibodies in PBS containing
0.5% BSA,
0.05% poly sorbate 20, 15 ppm Proclin, pH 7.4 is added to the plates and
incubated for 2 h.
For enhanced binding sensitivity due to avidity, immune complexes are formed
using anti-
human antibody. Bound antibody is detected with HRP-conjugated goat anti-human
kappa
(Southern Biotech) using Ultra TMIB substrate as described in Example 1. The
reaction is
terminated and the plate is read as described above. The dose-dependent
binding curve of the
wild type antibody (no Fc modifications) is fitted with GraphPad Prism
(Sunnyvale, CA) four
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parameter curve fitting program. The relative affinity of the variant vs. the
wild type is
estimated by dividing the equivalent ng/ml wild type concentration at the
appropriate
concentration.
1004211 In addition, the variants are tested directly in Fc effector
bioassays (Promega)
following manufacturer's directions. These assays include iFyyPdia-H ADCP
IBioassay
(promega cat #C19901), ADCC Reporter Bioassays, EcyRilla F Variant (Promega,
cat
#Ci9798), ADCC Reporter Bioassays, FeyRIIIa V Variant (Prom ega, cat. #G7015).
The
variants are tested both as monomeric Ig and as sin& t immune complexes ( iCs)
by using an
anti-hal-1g antibody to form small ICs.
1004221 A Europium based ADCC assay is performed. Briefly, peripheral blood
lymphocytes (PBLs) are isolated by Ficoll Paque Plus gradient centrifugation.
The PBLs are
collected, washed with RP1VI1640, 10% FCS and resuspended in cell culture
medium. The
cells are diluted to 2.5 x 106 cells/ml. Target cells are labelled with BADTA
(2,2':6',2"-
terpyridine-6,6"-dicarboxylic acid acetoxymethylester): Cells are harvested by
adding
Accutase (Millipore), washed once and diluted to 1 x 106 cells/ml. Next, 2.5
jL BADTA is
added per 1 x 106 cells and incubated for 35 min at 37 C with 5% CO2. After
labelling the
cells are diluted with 10 ml culture medium, centrifuged at 200 x g for 10 min
and
supernatant aspirated. This step is repeated 3X with culture medium/2
mMProbenicid and
the sample is diluted to 1 x 10 cells/ml, centrifuged at 300 x g for 5 min,
supernatant taken
off and 50 IAL pip etted into the wells intended for the background controls.
The final ratio of
effector (PBL) to target cells is 25:1.
1004231 Controls include: (1) Background: the 501xL aliquot, diluted
with 100 pt
medium, (2) Spontaneous lysis: 50 pt of the labelled target cell suspension
plus 100 L
culture medium, incubated 2 h at 37 C, (3) Maximal lysis: 50 L/well of the
labelled target
cell suspension plus 100 L Triton X-100 (0.5% in PBS) incubated 2 h at 37 C,
(4) Lysis
control without antibodies: 50 L/well of the labelled target cell suspension
and 50 IAL
culture medium plus 50 !IL of effector cells incubated 2 h at 37 C, (5) Lysis
control without
effector cells: 50 pi/well of the labelled target cell suspension; add 50 L,
culture medium
plus antibody at highest concentration used and incubate 2 hat 37 C.
At the end of the incubation period the 96 well plate is centrifuged at 100
rpm. 20 pi, of each
supernatant is transferred into an OptiPlate HTRF-96 (Packard) and 200 p,L
Europium
solution is added and incubated for 15 min on a shaker. Fluorescence is
measured as for time
resolved fluorescence and spontaneous release and specific release are
calculated.
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1004241 A CDC assay is performed. Briefly, target cells are washed and diluted
to 1 x 105
cells/ml and 100 L/well (104 cells) are added to a 96-well flat bottom
microtiter plate. A
titration curve of the test antibody is created using serial dilutions,
beginning at 1 g/mL.
Antibody is added to the plate, mixed gently, and is then placed at 37nC/5%
CO2 incubator
for 30 min. Next, 25 pL freshly dissolved baby rabbit complement (Cedarlane
CL3441, 1 ml
lyophilized, dilute freshly in 4 ml double distilled water) is added, mixed
gently, and the plate
is incubated at 37 C/5% CO2 incubator for 30 min. After the incubation period
50 L
supernatant is taken off and 100 L Cell Titer Glo. reagent (Promega Corp.) is
added to the
remaining 100 1_, supernatant. The plate is placed on an orbital shaker for 2
min, 100
L/well is transferred into a black luminescence microtiter plate (Costar) and
luminescence is
measured. Controls included: (1) medium control (target cells plus 50 L
medium), (2)
maximal lysis control (target cells plus 501_iL 0.5% Triton X-100), (3)
complement control
(target cells plus 25 L medium plus 25 pt complement).
1004251 As provided and described herein, Fc variants were designed to
diminish effector
function and subsequently tested for the ability to (i) effectively be
purified/manufactured
(Table 11), (ii) reduce antibody-dependent cell-mediated cytotoxicity (ADCC),
and (iii)
reduce complement-dependent cytotoxicity. 'lest articles tested comprise heavy
chain SEQ
ID NOs: 368-380. Heavy chains used were paired with a light chain comprising
SEQ ID NO:
381. ELISA titration profiles and EC5Os were generated against recombinant
TL1A antigen
("EC50", Table 12). Interestingly, Fc mutations did affect purity, as measured
by monomer
content, for select mutations/Fc variants (Table!!, wild-type IgG1 control).
1004261 Reduction of CDC activity
1004271 Test articles were evaluated for CDC activity, compared to negative
control
Human IgG4 isotype control, on TL1A-expressing HEK293 target cells. Rituxan
(anti-CD20)
was used as a positive technical control on CD20-expressing Raji cell. All
test articles were
used at a final top concentration of 10 pg/mL followed by a five-fold dilution
series (7 points
total), in addition to a no treatment control, in triplicate. Cells were
incubated with test
articles for 15 minutes at 37 C, then treated with human complement, at a
final concentration
of 25%, for 3 hours at 37 C, 5% CO2. Following incubation, cells were washed
and
resuspended in Propidium Iodide (P.I.) at a final concentration of 5 1.1g/mL
prior to flow
cytometry analysis. Total cells were examined by flow cytometry during sample
acquisition.
Data were plotted on an XY chart, graphing percentage P.I. positive cells
against the log of
the concentration and fit to a non-linear regression curve. Cell cytotoxicity
in the presence of
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all test articles was not distinguishable from cell cytotoxicity in the
presence of isotype
control (Table 12). CDC bioactivity was observed on Raji target cells with
Rituxan
treatment.
Table 11. anti-TL1A antibodies tested for reduced effector function
Purity
Fc SEQ Heavy Chain
Class
ID NO SEQ ID NO InghilL mg SDS-
SEC-
PAGE HPLC
326 368 2.65 10.60 95%
90%
323 369 1.15 12.65 95%
92%
329 370 3.22 10.62 90%
89%
IgGl, protein 338 371 1.61 11.27 95%
92%
variants 344 372 3.43 10.29 95%
91%
332 373 1.51 15.10 95%
93%
363 374 2.85 11.40 95%
92%
364 375 1.55 10.85 95%
92%
IgGl, glycan 356 376 2.33 9.32 90%
90%
knock-out 350 377 1.36 12.24 95%
92%
365 378 1.78 19.58 95%
82%
IgG4 366 379 2.33 18.64 90%
81%
367 380 5.08 15.24 95%
90%
Control 3.70 5.55 95%
97%
Table 12. Effector function of anti-TL1A antibodies
Fc SEQ Heavy Chain EC50
Class ADCC CDC
ID NO SEQ ID NO (nM)
326 368 0.222 ND ND
323 369 0.215 100 ng/mL ND
329 370 0.188 ND ND
IgGl, protein 338 371 0.220 10 pg/mL ND
variants 344 372 0.346 ND ND
332 373 0.347 ND ND
363 374 0.329 ND ND
364 375 0.330 ND ND
IgGl, glycan 356 376 0.340 ND ND
knock-out 350 377 0.293 ND ND
365 378 0.299 ND ND
IgG4 366 379 0.324 ND ND
367 380 0.252 ND ND
[00428] Reduction of CDC activit),
[00429] An antibody-dependent cell-mediated cytotoxicity (ADCC) reporter assay
was
performed for the characterization of test articles and IgG4 Isotype control
on HEK 293
TL1A cells. A reporter cell line engineered to express human Fc-gamma-RIlla
V158 (high
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affinity) served as effector cells.
1004301 Test articles were evaluated with a top concentration of 10 ug/mL (log
dilution for
7 points total, in addition to no test article control). Treatment conditions
were tested in
triplicate, effector and target cells were co-cultured for 6 hours at 37 C
with 5% CO2. Raji
target cells were used as a positive control, with Rituxan treatment at a top
concentration of
ug/mL, 7-point log dilution series, and no treatment control. Test article 502
treatment
resulted in dose-dependent increase in luciferase reporter gene activity, and
5044 treatment
resulted in increase of reporter activity at the highest tested concentration.
The rest of the test
articles did not induce reporter activity (Table 12).
Example 4: Characterization of potency and species selectivity in whole blood
assay
1004311 The relative potency of a panel of candidate antibodies was first
assessed by
determining the inhibition of interferon gamma release in human blood using
the antibodies
at 1 and 10 nM. All of the antibodies displayed potent activity, with A219
appearing to be
one of the most potent candidates (Table 4).
Table 4. Inhibition of interferon gamma release in human blood with anti-TL1A
Clone '1/0 Inhibition at 1 nIVI Ig "A Inhibition at 10 nIVI
Ig
A147 51.3 72.4
A212 46.8 71.2
A213 48.6 69.8
A217 46.0 72.2
A219 59.8 75.2
A220 36.9 63.2
[00432] Next, three of the variants were characterized for inhibition of
interferon gamma
release in human blood using multiple human blood donors and testing the
antibodies across
a broader range of concentrations (0.01 ¨ 100 nM). Representative inhibition
profiles of
variants A212, A213 and A219 are shown in FIG 2. The mean IC50 values for
these variants,
and a control antibody termed 1D1, for the inhibition of interferon gamma
release from
multiple human donors is shown in Table 5.
Table 5. IC50 values
Clone Mean SD
A212 51.3 72.4
A213 46.8 71.2
A219 48.6 69.8
1D1 46.0 72.2
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Example 5: Properties of an anti-TL1A antibody
1004331 Physical and chemical properties of the anti-TL1A antibody A219 are
shown in
Table 18. Physical and chemical properties of A219
Property Description
Molecular Weight 143,938 Daltons
Antibody class/subclass IgG1
A219 has an N¨ linked carbohydrate attachment at a single site, Asn296 of
Gly co sy lation
the heavy chain. The major gly cosylation species is GOF
Human TL1A 59.0 +/- 15.6 pM
'ILIA binding affinity (KD)2 Cynomolgus TL1A 36.3 +1-12.8 pM
Murinc TL1A No significant binding
No bindingto the closely related human cytokines TNFSF6 (FasL), TNFSF10
Specificity
(TRAIL) and TNFSF14 (LI GHT) tested as recombinant proteins
Extinction coefficient3 1.410 mg-l.mLem-'
pI 8.8
1 Unglycosylated calculated molecular weight from the amino-acid sequence
2 Three independent measurements, +/- standard deviation
3 Calculated extinction coefficient from the amino-acid sequence
Example 6: Animal model of colitis
1004341 The efficacy of anti-TL1A antibodies in animal models of colitis is
performed.
Anti-TL1A antibodies are tested in rodent models of acute colitis induced by
intrarectal
administration of di- or tri-nitrobenzenesulfonic acid (D/TNBS) or oxazolone,
and chronic
colitis induced by administration of DSS in drinking water or transfer of
CD45RB T cells.
DNBS and oxazolone induce localized ulceration and inflammation. DSS
administration
induces robust generalized inflammation of the intestinal tract characterized
by erosive
lesions and inflammatory infiltrate. Symptoms of all these models usually
include diarrhea,
occult blood, weight loss and occasionally rectal prolapse. In a prophylactic
model, antibody
treatment begins at the start of administration of the colitis-inducing
compound. In a
therapeutic model, antibody treatment begins several days after commencement
of induction.
The effect of the treatment on weight, stool consistency and occult blood, as
well as
microscopic effects on epithelial integrity and degree of inflammatory
infiltrate is
determined. Daily clinical scoring is performed based on stool consistency and
presence of
occult blood giving a disease activity index (DAI) score.
Example 7: Summary of pharmacology, pharmacokinetic, and toxicology studies
1004351 The anti-TL1A antibody A219 binds human tumor necrosis factor-like
cytokine
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1A (TL1A) with high affinity and specificity and neutralizes TL1A functional
activity in in
vitro and ex vivo cell-based assays. A219 binds to both human and cynomolgus
TL1A with
similar affinity (KD values of 0.06 nM and 0.04 nM, respectively). In
addition, A219 is
specific for TL1A and does not bind to other tumor necrosis factor super
family (TNFSF)
members. A219 blocks human TL1A-induced caspase activation in the TF-1
functional assay
with an 1050 of 0.27 nM. A219 inhibits TL1A-mediated interferon gamma release
from
peripheral blood mononuclear cells (PBMCs) in whole blood from monkeys
administered
doses of >0.056 mg/kg. In addition, a dose-dependent increase in circulating
soluble (sTL1A)
concentrations was observed at all dose levels in these monkeys. This suggests
that systemic
sTL1A levels may be a useful PD marker for target engagement by A219.
1004361 The nonclinical pharmacokinetics (PK) of A219 were characterized in
the monkey
and support the proposed once every other week dosing regimen in humans. The
nonclinical
PK of A219 is as expected for a monoclonal antibody that exhibits target-
mediated drug
disposition (TMDD) at lower doses and linear PK at higher dose levels that
saturate the
target-mediated route of clearance.
1004371 A219 was administered to monkeys once weekly via IV injection for up
to 6
weeks (7 total doses). Most, if not all, of the findings observed after IV
administration of
A219 to monkeys in the 6-week repeat-dose toxicity study were considered to be
secondary
to generation of ADA in response to administration of a foreign protein
(humanized
monoclonal antibody) to immunocompetent animals. Based on electrocardiograms
(ECGs),
daily and detailed weekly clinical observations, and microscopic evaluation of
the relevant
tissues/organs there were no cardiovascular, central nervous system (CNS) or
respiratory
system effects observed in monkeys during 6 weeks of once weekly IV
administration of
A219 at up to 300 mg/kg/week. The clinically relevant no observed adverse
effect level
(NOAEL) in this study was considered to be 300 mg/kg/week (the highest dose
tested). There
was no off-target binding of A219 noted in the tissue cross-reactivity study
with human or
monkey tissues. There was no A219-related cytokine release in the human PBMC
or whole
blood cytokine release assays, nor in monkeys during the 6-week repeat- dose
toxicity study.
A219 did not cause complement-dependent cytotoxicity (CDC) or antibody-
dependent
cellular cytotoxicity (ADCC) of target expressing cells in Fc effector
function assays.
Example 8: Biophysical properties of anti-TLIA antibodies at high
concentrations
1004381 The data for A219 anti-TL1A antibody properties in solution were
analyzed
together using a chemometric method termed partial least squares (PLS).
Detailed
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descriptions of PLS modeling have been published in, for example, Katz, M. H.
Multiyariate
Analysis: A Practice Guide for Clinicians. Cambridge University Press, New
York, pp. 158 -
162 (1999); Stahle, L., Wold, K., Multivariate data analysis and experimental
design in
biomedical research. Prog. Med. Chem. 1988, 25: 291-338; Wold S. PLS-
regression: a basic
tool of chemometrics. Chemom. Intell. Lab. Syst. 2001, 58: 109-130; and
Martens, H.;
Martens, M. Multivariate Analysis of Quality: An Introduction, Wiley and Sons,
Chichester,
UK (2001). The calibration sets (blue lines) use all data for the model, while
validation sets
(red lines) leave out one sample at a time and rebuild the model for an
assessment of
ruggedness.
1004391 The viscosity was measured using an mVROCTM viscometer by Rheosense
with
an A10 chip. The shear rates employed were about 1820 s-1. The viscometer was
temperature controlled using a ThermoCube thermoelectric chiller and the
samples were
delivered using a Hamilton 100 [IL syringe (81060). The accuracy of the
instrument was
verified using neat Isopropyl alcohol and measured at 25 C. Furthermore,
across the
concentration range tested, the percent increase in the HMW fraction as
measured by size
exclusion chromatography ranged from 0% to a 1.3% increase. HMW as used herein
refers
to high molecule weight antibody fraction, e.g., aggregated protein, and which
excludes
monomeric antibody.
1004401 Table 25 and Table 26 provide example formulations evaluated.
Table 25. Round 1 formulations
Form No protein pH phos His citrate acetate
NaC1 sorbitol
1 130 6.5 20 0 0 0 0
270
2 130 6.5 20 0 0 0 130
0
3 130 6.5 0 20 0 0 0
270
4 130 6.5 0 0 20 0 0
270
130 6.0 0 10 0 0 50 180
6 130 5.5 0 20 0 0 130
0
7 130 6.0 0 0 20 0 50
180
8 130 6.0 0 0 10 0 0
270
9 130 7.5 20 0 0 0 50
180
130 7.0 0 0 0 0 0 270
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11 130 5.5 0 0 0 0 50 180
12 130 7.5 20 0 0 0 130 0
13 130 5.0 0 10 0 0 0 270
14 130 5.0 0 0 0 20 50 180
15 130 5.0 0 0 0 20 130 0
16 130 4.5 0 0 0 10 0 270
Table 26. Round 2 formulations
Form
HP-b-
1 CD
protein pH acetate His sucrose sorbitol NaC1 Gly ArgHC1LysHC1 o
1 130 5.0 20 0 0 0 130 0 0 0 0
2 130 5.0 20 0 0 180 50 0 0 0 0
3 170 5.5 0 20 0 0 0 270 0 0 0
4 170 5.0 10 0 0 180 0 0 50 0 0
150 5.0 0 0 270 0 0 0 0 0 0
6 150 5.5 10 0 220 0 0 0 0 0 75
7 170 4.5 10 0 0 0 0 270 0 0 0
8 170 5.5 0 0 0 0 100 0 0 0 50
9 150 5.0 0 20 0 220 0 0 25 0 0
150 5.5 0 10 150 0 50 0 0 0 0
11 170 5.5 0 0 0 0 0 120 0 50 0
12 130 6.0 0 20 220 0 0 0 0 25 0
13 170 5.0 0 20 0 0 50 0 0 0 100
14 170 5.5 20 0 0 180 0 0 50 0 0
1004411 Viscosity
1004421 FIG. 3A depicts the comparison between the predicted and measured
viscosity,
where viscosity is in units of mPa-s. FIGS. 3B-3D demonstrates viscosity as a
function of
antibody concentration and pH. Antibody concentration ranged from greater than
about 125
mg/mL to greater than about 170 mg/mL. pH ranged from less than 5.0 to about
7.5.
Concentration dependence is evident, with very low viscosities (e.g., as
indicated by a
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viscosity less than 5 mPa-s or 7mPa-s). All formulations show low viscosities
(< 10 mPa-s),
even at 170 mg/mL. FIG. 3E depicts the effects of pH versus acetate
concentration at an
antibody concentration of 150 mg/mL on viscosity. There is a slight pH
dependence, with
minimal viscosity near pH 6. FIG. 3F shows the effect of sucrose versus NaCl
on viscosity at
a pH pf 5.5 and an antibody concentration of 150 mg/mL. NaCl helps reduce
viscosity, while
HP-b-CD significantly increases viscosity. FIG. 3G depicts the effect of
ArgHC1 versus
Ly sHC1 at a pH of 5.5. ArgHC1 increases viscosity slightly, while LysHC1 has
small effect.
The formulated anti-TL1A antibodies also exhibited low viscosity (less than 16
mPa-s) at 200
mg/ml anti-TL I A.
[00443] Aggregation
[00444] FIG. 4A depicts the PLS1 model for the effect on high molecular weight
(BMW)
aggregates at 2C and 25 C. FIGS. 4B-4E depict the effect of different
parameters on
aggregation. The response surface shows the increase in HMW overtime. FIG. 4B
depicts
the effect of pH versus acetate on aggregation at an antibody concentration of
150 mg/mL. A
lower pH leads to less aggregation (by SEC), using the PLS12 model, including
all
formulations with an increase in HMW species (%) by SEC as the endpoint FIG.
4C depicts
the effect of sucrose versus NaCl concentration on aggregation at a pH of 5.5
and an antibody
concentration of 150 mg/mL. FIG. 4D depicts the effect of ArgHCl versus Ly
sHC1 on
aggregation at a pH of 5.5 and an antibody concentration of 150 mg/mL. FIG. 4E
depicts the
effect of sucrose concentration versus LysHC1 concentration over time at a pH
of 5.5 and an
antibody concentration of 150 mg/mL with 20 mM acetate. Sucrose, sorbitol, and
Lys reduce
aggregation. The formulated anti-TL1A antibodies also exhibited low
aggregation at 200
mg/ml anti-TL1A.
[00445] Loss of Major Peak by Cation Exchange Chromatography CEX
[00446] FIG. 5A depicts the predicted versus measured loss of main peak at 2
weeks and
25 C. FIGS. 5B-5E depict the effect of different parameters on the loss of
main peak. The
response surface indicates the percent loss of the main peak. FIG. 5B depicts
the effect of pH
and protein concentration on the loss of main peak in the CEX profile. The
optimum pH for
reducing loss of main peak by CEX is between 5 and 6. FIG. 5C depicts the
effect of pH and
acetate concentration on the loss of main peak in the CEX profile, at an
antibody
concentration of 150 mg/mL. FIG. 5D depicts the effect of sucrose and NaCl
concentration
on the loss of main peak in the CEX profile, at an antibody concentration of
150 mg/mL and
a pH of 5.5. FIG. 5E depicts the effect of Ly sHC1 and sucrose concentration
on the loss of
main peak in the CEX profile, at an antibody concentration of 150 mg/mL, pH of
5.5, with 20
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mM concentration of acetate. The formulated anti-TL1A antibodies also
exhibited low levels
of loss of main peak at 200 mg/ml anti-TL1A.
Example 9: The effects of Polysorbate 20 or Polysorbate 80 on storage
stability
1004471 After two rounds of formulation screening based on storage stability
at different
temperatures, Round 3 was designed to evaluate the interfacial sensitivity of
two different
base formulations in the presence (and absence) of varying amounts of
polysorbate: PS20 and
PS80. Repeated freeze-thaw (FIT) stress and agitation (Ag) were used as stress
conditions.
Two base formulations of anti-TL I A A219 at -200 mg/ml were evaluated, as
seen in Table
15.
Table 15. Formulation design
Form Form pH acetate protein Sucrose NaC1 LysHC1 PS
PS
No (mM) (mg/ml) (mM) (mM) (mM) 20 80
(/0)
(/0)
1 1 5.3 20 200 240 0 25 0
0
1-A 1 5.3 20 200 240 0 25 0.01
0
1-B 1 5.3 20 200 240 0 25 0
0.01
1-C 1 5.3 20 200 240 0 25 0.02
0
1-D 1 5.3 20 200 240 0 25 0
0.02
1-E 1 5.3 20 200 240 0 25 0.05
0
1-F 1 5.3 20 200 240 0 25 0
0.05
2 2 5.3 20 200 0 140 0 0
0
2-A 2 5.3 20 200 0 140 0 0.01
0
2-B 2 5.3 20 200 0 140 0 0
0.01
2-C 2 5.3 20 200 0 140 0 0.02
0
2-D 2 5.3 20 200 0 140 0 0
0.02
2-E 2 5.3 20 200 0 140 0 0.05
0
2-F 2 5.3 20 200 0 140 0 0
0.05
1004481 Results are depicted in Tables 16-17 and FIGS. 6A-6B. FIG. 6A depicts
the loss
of monomer by size exchange chromatography (SEC) with agitation. FIG. 6B
depicts the
loss of monomer by SEC with freeze-thaw. The results demonstrate that both PS
20 and PS
80 surfactants provide a stabilization benefit. There was very weak
concentration dependence
observed for both surfactants. Additionally, there was no appreciable chemical
damage
during short-term stress seen by CEX.
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Table 16. Visual Appearance
Form QS (Ag) Control FT
1 Clear Cloudy Clear Clear
1-A Clear Clear Clear Clear
1-B Clear Clear Clear Clear
1-C Clear Clear Clear Clear
1-D Clear Clear Clear Clear
1-E Clear Clear Clear Clear
1-F Clear Clear Clear Clear
2 Clear Cloudy Clear Clear
2-A Clear Clear Clear Clear
2-B Clear Clear Clear Clear
2-C Clear Clear Clear Clear
2-D Clear Clear Clear Clear
2-E Clear Clear Clear Clear
2-F Clear Clear Clear Clear
Table 17. SEC results
QS samples Agitation Samples
Form HMW Rel. Main Peak LMW Rel. HMW Rel. Main Peak LMW Rel.
Area (%) Rel. Area Area (%) Area (%) Rel. Area Area
(%)
(Im) (OA))
1 1.99 97.97 0.05 3.37 96.59 0.04
1-A 2.01 97.94 0.05 1.99 97.94 0.07
1-B 2.08 97.87 0.05 2.00 97.94 0.06
1-C 2.01 97.94 0.05 1.97 97.97 0.06
1-D 2.04 97.92 0.05 1.97 97.97 0_07
1-E 2.03 97.93 0.05 1.98 97.95 0.08
1-F 1.97 97.99 0.04 1.94 97.99 0.07
2 2.24 97.71 0.05 3.80 96.17 0.03
2-A 2.21 97.75 0.04 2.22 97.71 0.07
2-B 2.21 97.74 0.05 2.25 97.68 0.07
2-C 2.25 97.70 0.05 2.32 97.60 0.08
2-D 2.19 97.76 0.05 2.31 97.62 0.08
2-E 2.20 97.75 0.05 2.35 97.57 0.09
2-F 2.21 97.74 0.05 2.23 97.70 0.07
Example 10: Long term stability
1004491 Formulation 1(150, 175, or 200 mg/ml of anti-TL1A; 20 mM acetate; pH
5.3; 240
mM sucrose; 25 mMLysHC1; 0.02% PS 20) and Formulation 2(150, 175, or 200 mg/ml
of
anti-TL1A; 20 mM acetate; pH 5.3; 220 mM sucrose; 40 mM NaCl; 0.02% PS 20) are
tested
for long-term stability over 6 months. One set of formulations is stored at 5
C and one set of
formulations is stored at 25 C. pH, osmolality, protein concentration, and
viscosity are
measured at the beginning of the study and after 6 months. SEC, CEX, FlowCAM
and visual
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appearance are used to monitor the stability at the beginning of the study and
at 1 month, 2
months, 3 months, and 6 months into the study.
Example 11: Pharmaceutical properties and formulation
[00450] Formulations of anti-TL1A A219 were prepared. An A219 formulation is a
clear
to slightly opalescent, colorless to slightly yellow liquid that is
essentially free of foreign
matter, supplied as 8.4 mL of a 60 mg/mL solution in a 10 mL SCHOTT Fiolax
Type I
Tubular Glass Vial sealed with a West Bromobutyl Rubber Stopper and West Flip-
Off.
[00451] The qualitative composition of A219 is provided in Table 19 below.
Table 19. Example composition of anti-TL1A
Ingredient Quality Standard Function
A219 Drug Substance cGMP Active
Ingredient
Sodium Phosphate, m ono b asic monohydrate USP, FCC, endotoxin tested
Buffer
Sodium Phosphate, dibasic Heptahydrate USP, FCC, endotoxin tested
Buffer
Sucrose USP/NF, EP, JP Stabilizer
Glycine BP, EP, JP, USP Stabilizer
Poly sorbate-20 NF, multi-compendial Surfactant
Water for Injection (WFI) USP/NF Diluent
BP = British Pharmacopoeia; cGMP = current Good Manufacturing Practice; EP =
European Pharmacopeia; FCC =
food chemicals codex; NF = National Formulary; JP = Japanese Pharmacopeia; USP
= United States Pharmacopeia.
[00452] Drug product preparation
[00453] Solutions of A219 may foam. Therefore, shaking or excessive
agitation of vials is
avoided. Additionally, care is taken to ensure the sterility of the prepared
solution, as the drug
product may not contain antimicrobial preservatives or bacteriostatic agents.
A sufficient
excess of drug product may be included in each single use vial to account for
withdrawal
losses.
[00454] Dilution of A219 injection is performed using sterile
disposable latex -free
syringes. An 18 gauge, 1.5 inch sterile needle is used for withdrawal from the
vial. Prior to
IV administration, A219 injection is diluted in a polyvinyl chloride (PVC) IV
bag containing
0.9% Sodium Chloride Injection (normal saline [NS]), using aseptic technique,
to prepare a
dosing solution with a A219 concentrations between 0.01 and 8 mg/mL. The
product is
infused at the protocol-specific dose(s) and rate(s) through a PVC IV solution
infusion set
with a sterile, nonpyrogenic 0.2 j.tm polyethersulfone in line filter. It is
not administered as W
push or bolus injection.
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100455] Storage conditions and use conditions
1004561 A219 formulated at 500 mg/vial (60 mg/mL) is stored in a refrigerator
at a
temperature of 2 -8 C (38 -46 F).
Example 12: A219 Binding selectivity
1004571 The predicted TL1A protein sequence in human was compared to the
mouse, rat
and cynomolgus monkey sequences. Mouse, rat and monkey protein sequences were
64%,
66%, and 98% homologous to human TL1A, respectively.
1004581 The binding of A219 to mouse, rat, cynomolgus monkey, and human
recombinant
TL1A protein was assessed in an ELISA. As shown in FIG. 7A, A219 binds to
human and
monkey TL1A with sub-nanomolar IC50 values of 0.33 nM and 0.47 nM,
respectively. In
contrast, A219 did not bind to mouse or rat TL 1A protein.
1004591 A219 binding affinity and kinetics for recombinant human and monkey
TLIA
protein was assessed using surface plasmon resonance (SPR). A219 binds to
human and
cynomolgus TLIA with KD values of 0.06 nM and 0.04 nM, respectively.
1004601 The binding of A219 to membrane-bound 'TL1A was assessed using human
embryonic kidney 293 cells stably transfected with human TLIA (TNFSF15/HEK293
cells).
A219 binds to membrane-bound TLIA expressed on the surface of TNFSF15/HEK293
cells
in a dose- dependent manner with an EC50 value of 17.4 nM. There was no
binding to the
parental HEK293 cells.
1004611 ILIA is the only known ligand for its functional receptor DR3. TL1A is
also
capable of binding to Decoy receptor 3 (DcR3), a soluble TNF receptor without
a
transmembrane domain. The binding of A219 to other known ligands of DcR3,
including
TNFSF6 (FasL), TNFSF10 (TRAIL) and TNFSF14 (LIGHT) were assessed by ELISA.
A219
did not bind to these TNF family members when tested at concentrations nearly
1,000-fold
above the EC50 of the respective positive control antibodies.
Example 13: In vitro functional activity of anti-TL1A
1004621 The ability of A219 to prevent DR3 -mediated caspase activation by
either human
or monkey TLIA was assessed in cycloheximide-treated TF-1 cells. TF-1 cells
are human
erythroleukemic cells that natively express DR3, the functional receptor for
TLIA. Human
and cynomolgus TLIA proteins were both capable of binding and activating the
DR3
receptor on human TF-1 cells, resulting in intracellular caspase activation
and apoptosis.
A219 inhibited human and monkey TLIA-induced caspase activation in TF-1 cells
with IC50
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values of 0.27 nM and 0.59 nM, respectively.
1004631 PBMCs in whole blood collected from cynomolgus monkeys release IFN-y
when
stimulated with immune complex in the presence of IL-12 and IL-18. This
enhancement of
IFN-y secretion reflects immune complex-driven TL1A production by PBMCs. The
ability of
A219 to inhibit IFN-y release under these conditions was assessed in vitro in
freshly collected
monkey whole blood.
1004641 IFNI, levels were measured in whole blood after stimulation in vitro
with immune
complex in combination with IL-12 and IL-18, and in the presence of increasing
concentrations of A219 (concentration range 0.05 nM to 100 nM). IFN-y release
was
inhibited by A219 in a dose-dependent manner in monkey whole blood. The mean
IC50 and
IC90 values for the inhibition of the IFN-y response were 1.54 nM (289 ng/mL)
and 17.7 nM
(3321 ng/mL), respectively.
Example 14: In vivo pharmacology
1004651 In a single dose PK/PD study with an 11 day follow on period in
monkeys, A219
was administered by IV bolus to 3 animals/group (mixed sexes) at doses of 0
(i.e., 0.56
mg/kg human IgG1 isotype control), 0.0056,0.056 and 0.56 mg/kg. The A219 doses
tested in
the study were selected to result in A219 serum concentrations of
approximately 1-, 10-, or
100-fold of the IC50 based on results from the in vitro monkey whole blood IEN-
y assay.
Blood was collected to assess PK, sTL1A concentrations, and in vitro whole
blood IFN-
release. The effect of A219 on the inhibition of TL1A-mediated IFN-y release
at 0.0056
mg/kg could not be evaluated due to the insufficient increase in IFN-y release
at the pre-dose
baseline. Administration of 0.056 mg/kg or 0.56 mg/kg A219 resulted in nearly
full inhibition
of IFN-y release at 1-hour post-dose, relative to the isotype control. At 264
hours (11 days)
post-dose, inhibition of IFN-y release was less than at 1 hour post-dose but
persisted in the
0.56 mg/kg A219 group. Inhibition of TL1A-mediated IFIN--1 release was dose-
dependent at
doses >0.056 mg/kg where the observed exposure at 0.056 mg/kg was >6.8-fold
above the in
vitro whole blood assay IC50 of 1.54 nM (289 ng/mL).
1004661 Following administration of 0.0056, 0.056 or 0.56 mg/kg A219, the mean
concentration of sTL1 A increased in a dose-dependent manner, by 3.6-, 10.4-,
and 14.4-fold,
respectively, relative to the isotype control antibody at 6 hours post-dose
(FIG. 7B). The
increase in TL1A concentrations across all A219 dose groups was observed at
the earliest
timepoint tested (6 hours post-dose) and was sustained until the last
timepoint (264 hours
post-dose).
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[00467] Safety pharmacology
[00468] Cardiovascular, CNS, and respiratory safety pharmacology endpoints
were
incorporated into a 6- week repeat-dose IV toxicity study in monkeys.
[00469] There were no functional effects on the cardiovascular system as
assessed by ECG
measurements in the pre-dose phase and during Weeks 1 and 6 of the dosing
phase, and by
microscopic evaluation of the heart and major blood vessels at 300 mg/kg/week.
There were
no changes related to A219 administration in heart rate, no cardiac rhythm
abnormalities or
qualitative or quantitative ECG changes, and no microscopic findings noted in
the heart that
would have impacted cardiac function.
[00470] There were no functional effects on the CNS based on daily clinical
observations
and detailed weekly examinations that included: observing the animal's
behavior and
movement while approaching the cage, autonomic activity (e.g., lacrimation,
piloerection,
pupil size), changes in posture and reactivity to handling, as well as
presence of clonic or
tonic movements, behavioral /psychological abnormalities, circling, and self-
mutilation at
300 mg/kg/week. There were no microscopic findings in the brain or nervous
system that
would have impacted the CNS function.
[00471] There were no effects on the respiratory system based on daily
clinical
observations of animal respiration and detailed weekly examinations that
included monitoring
for unusual respiratory patterns at 300 mg/kg/week.
[00472] In conclusion, there were no functional cardiovascular, CNS or
respiratory system
findings observed in monkeys during 6 weeks of once weekly IV administration
of A219 at
300 mg/kg/week.
[00473] Systemic pharmacokinetics in animals
[00474] The serum PK and toxicokinetics (TK) of A219 were investigated in the
monkey,
to support dose selection for the pivotal 6-week toxicity study and to aid in
projecting the
appropriate starting dose in humans. IV dosing was used in all in vivo
studies.
[00475] A single IV dose PK/PD study in monkeys was performed to characterize
the PK
profile and the associated PD effects of A2119 at dose levels relevant to
projecting the first-in-
human starting dose. PD results are summarized previously. The PK of A219 was
nonlinear
over the 0.0056,0.056, and 0.56 mg/kg dose range, which is consistent with the
expected
target-mediated drug disposition (TMDD) for a monoclonal antibody to a
membrane-bound
target. AUC values increased in a greater than dose-proportional manner, and
where it could
be estimated, t1/2 increased with increasing dose (Table 20).
Table 20. Mean (SD) PK Parameters after a single IV dose to cynomolgus monkeys
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Dose (mg/kg) Cmax ( g/mL) AUCO-t (hrItg/mL) t1/2
(hr)
0.0056 0.142(0.0181) 0.411 (0.297) 12.1a
0.056 1.58 (0.245) 79.7(13.5) 1200
63.6(11.9)
0.56 12.8 (1.35) (234) 113b
Cmax = maximum observed concentration; AUCO-t = area under the concentration
versus time
curve from time 0 to the timepoint with the last measurable concentration;
t1/2 = terminal
half-life
N = 3 unless otherwise noted
a N = 1 (insufficient characterization of the terminal phase of the
concentration versus time profile to
estimate this parameter in the other two animals)
b N = 2 (insufficient characterization of the terminal phase of the
concentration versus time profile to
estimate this parameter in the third animal)
1004761 TK and immunogenicity were evaluated in cynomolgus monkeys as part of
a 2 -
dose non-GLP PK/tolerability study and a GLP 6-week repeat-dose toxicity
study.
1004771 In the 2-dose PK study, monkeys (N = 1/sex/group) received 2 doses of
A219 via
IV bolus administration one week apart at dose levels of 30, 100, and 243
mg/kg. Following
the first (Day 1) or second (Day 8) dose, exposure based on mean Cmax
increased in an
approximately dose- proportional manner. Mean AUCO-t values increased in a
dose-
dependent, but not necessarily dose-proportional manner after the first and
second dose.
1904781 In the Gil' 6-week repeat-dose toxicity study, monkeys (N =3-
5/sex/group)
received A219 via IV bolus administration at dose levels of 0, 30, 100, or 300
mg/kg once
weekly for 7 doses. Exposure to A219 was comparable in male and female monkeys
following single and repeat dosing (differences in mean Cmax and AUC values
were less
than 2-fold). A219 exposure increased in an approximately dose-proportional
manner after
single and repeat dosing. Accumulation was observed after repeat once weekly
dosing at all
dose levels (serum exposure after the last dose (Day 42) was approximately 1.5
to 2.3-fold
higher than that observed after the first dose; Table 21).
Table 21. Mean (SD) TK Parameters after repeat once weekly IV dosing to
cynomolgus
monkeys
Dose
Day Parameter Units 30 mg/kg 100 mg/kg 300 mg/kg
Cm ax p.g/mL 743 (115) 2500 (433) 8760(1710)
1 AUCO-24hr hr* ug/mL 14500 45400 (4970) 154000
(27700)
AUCO- hr*ng/mL 61000 205000 (37600) 684000
(110000)
Cmax p.g/mL 1490(182) 5530(1270)
13800(3320)
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AUCO-24hr hr*pg/mL 28700 106000 (10500) 267000
(82900)
ARCmax 212(0667) 2.25 (0.517) 1_59
(0.421)
42 ARAUCO- 2.01 (0.364) 2.34 (0.141) 1.73
(0.522)
AIJCO-ta hr*pg/mL N/A N/A 1600000
(970000)
tv,a hr N/A N/A 38.7
(3.76)
Mean values were calculated based on males and females combined.
Cmax = maximum observed concentration; AUCO-24hr = area under the
concentration versus time
curve from time 0 to 24 hr postdose; AUCO-168hr = area under the concentration
versus time curve
from time 0 to 168 hr postdose; AUCO-t = area under the concentration versus
time curve from time 0
to the timepoint with the last measurable concentration; ARCmax = accumulation
ratio based on
Cmax; ARAUCO-24hr = accumulation ratio based on AUCO-24hr; t1/2 = terminal
half-life
N = 3 males and 3 females in the 30 and 100 mg/kg dose groups and 5 males and
5 females in the 300
mg/kg dose group.
a Estimated in recovery animals only (N = 2/sex).
Example 15: Toxicology
[00479] A219 was assessed in a series of in vitro and vivo toxicity
studies outlined in
Table 22. The IV route of exposure was selected for the in vivo studies. The
weekly dosing
regimen used in the definitive 6-week repeat-dose monkey toxicity study was
selected based
on the half-life of A219 in monkeys and was designed to have a similar or more
intensive
dosing regimen than the clinical dosing regimen.
Table 22. Overview of the toxicology program
Study Concentrations or Doses
6-Week IV Toxicity in Monkeys with a 6- 0,30,100,300
Week Recovery mg/kg/week
Tissue Cross-Reactivity in Monkey 0,0.625,1.25,2.5 g/mL
and Human Tissues
Cytokine Release Assay Using Human 0, 0.0002to 2 mg/mL
Whole Blood
Cytokine Release Assay Using Human 0, 0.0002 to 2 mg/mL
PBMCs
Antibody Dependent Cellular 0, 0.0031 to 30000ng/mL
Cytotoxicity Assay
Complement Dependent Cytotoxicity Assay 0, 0.0031 to 30000ng/mL
PBM Cs =peripheral blood mononuclear cells
[00480] The monkey was selected as the pharmacologically relevant nonclinical
species
because of similar TL protein sequence homology and nearly equivalent binding
affinity
of A219 to monkey TL1A, as compared to human TL1A. A219 was also
pharmacologically
active with similar IC50 values after binding monkey or human soluble TL in an
in vitro
cell-based assay. In an in vitro assay using monkey whole blood stimulated to
express TL1A
with subsequently IFNI, release, the addition of A219 inhibited IFNI, release
in a dose-
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dependent manner. A similar inhibition of IFN-y release was observed when
blood from
monkeys administered A219 was used in the assay. Binding of A2 19 to mouse or
rat TL1A
was also assessed and A219 did not bind rat or mouse TL1A.
[00481] 2-Dose PK and tolerabilit), study in monkeys
[00482] Tolerability was assessed in a 2-week PK and tolerability study.
Monkeys
(1/sex/group) were administered A219 IV at 30, 100 or 243 mg/kg/week on Days 1
and 8.
A219 was well-tolerated up to the highest dose tested, and the only clinical
signs observed in
A219-treated animals were loose stools in all dose groups at multiple
observation timepoints.
Based on the small numbers of animals and no control group animals, the
relationship of the
loose stools to A219 administration could not be determined. There were no
A219-related
changes in body weight, clinical chemistry, or hematology parameters.
[00483] 6-Week repeat-dose study with a 6-week recovery in monkeys
[00484] A GLP repeat-dose toxicity study of 6 weeks duration (once-weekly
dosing) was
conducted with A219 in monkeys. A219 was administered by IV bolus to male and
female
monkeys (3/sex/group) at doses of 0 (vehicle control), 30, 100, or 300
mg/kg/week (7 doses
total). Additional animals (2/sex/group) at 0 and 300 mg/kg/week were assessed
after a 6-
week recovery period for the reversibility of any A219-related effects.
[00485] A219 was well-tolerated after 6 weeks of administration at doses up to
300
mg/kg/week. Based on these studies, NOAEL is 100 mg/kg/week for males and 30
mg/kg/week for females.
[00486] Human Cytokine Release Assays
[00487] PBMC Assay
[00488] The potential ability of A219 to trigger cytokine release in primary
human
PBMCs derived from 10 normal healthy donors was evaluated in soluble and wet-
coated
formats. A range of A219 concentrations from 0.00002 to 2 mg/mL were
evaluated. A human
IgG4 antibody and untreated samples were used as negative controls; anti-CD3
(OKT3)
antibody was used as positive controls. The levels of IL-2, IL-6, IL-10, TNF,
and INF- were
measured after PBMCs or were cultured with A219 for 24 hours. PBMCs from all
donors
induced IL-2, IL-6, IL-10, TNF, and IFN-y release in response to OKT3
treatment (positive
control). The IL-2 response of Donor 9 was lower but present. The IgG4
negative control
antibody induced no or low IL-2, IL-10, TNF, and IFN-y cytokine release under
any of the
tested conditions. The IgG4 negative control antibody induced IL-6 production
in several
donors, although not as robustly as the positive control treatment. Cytokine
release was either
not observed or only observed at very low levels in untreated samples from all
donors.
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[00489] A219 did not induce IL-2 and IFN- release under any of the tested
conditions.
A219 induced low levels of IL-10 and TNF release in some donors, but not above
levels
induced by the IgG4 negative control antibody and/or in untreated samples.
A219 induced IL-
6 release in several donors in the same range of induction as observed with
the IgG4 negative
control and/or in untreated samples in both stimulation formats, but the
responses were not
concentration dependent. Based on historical testing facility data for IL-6
induction, a
variable range of magnitude of responses has been observed for isotype and
other negative
control antibodies, as well as other test articles in subsets of donors that
are often not
concentration dependent. A219, IgG4 treatment-related and untreated PBMC
responses were
lower than the anti-CD3 positive control treatment-related responses.
Therefore, the induction
of IL-6 in this assay was likely not A219-specific but related to variation
that has also been
observed historically in the assay for this cytokine.
[00490] In conclusion, A219 did not induce IL-2, IL-6,
TNF, IFN- specific release
from PBMCs from 10 different donors in wet-coated plate or soluble formats
above that
observed for the IgG4 negative control antibody and/or untreated samples.
[00491] Whole Blood Assay
[00492] The potential ability of A219 to trigger cytokine release in human
whole blood
derived from 10 normal healthy donors was evaluated in soluble and wet-coated
formats. A
range of A219 concentrations from 0.00002 to 2 mg/mL were evaluated. A human
IgG4
antibody and untreated samples were used as negative controls; Staphylococcal
enterotoxin B
(SEB) were used as a positive control. The levels of IL-2, IL-6, IL-10, TNF,
and INF were
measured after whole blood was cultured with A219 for 24 hours.
[00493] Whole blood from all donors induced IL-2, IL-6, IL-10, TNF, and IFN-'y
release
in response to SEB treatment (soluble stimulation format). The IFN- response
of Donors 1,3,
and 8 was lower but present. In whole blood from most donors, the human IgG4
negative
antibody control induced no or low cytokine production under all tested
conditions. Cytokine
release was not observed in untreated whole blood samples of most donors.
Whole blood
from one donor (Donor 7) produced IL-6, IL-10, and TNF-a in response to
several
concentrations of soluble IgG4 negative antibody control. However, the
cytokine levels were
generally at or below the levels observed for the same donor in untreated
samples.
[00494] A219 did not induce any cytokine release under any of the tested
conditions in
nine donors. Stimulation with 0.02 mg/mL of soluble A219 induced release of
low levels of
IL-6, IL-10 and TNF in whole blood from Donor 7. A dose-response relationship
between
A219 concentration and cytokine levels was not observed for this donor, and
the cytokine
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levels were below those observed with the IgG4 negative control and/or in
untreated samples
from this donor. Therefore, the induction of IL-6, IL-10 and TNF in Donor 7
samples were
likely not A219-specific.
[00495] In conclusion, A219 did not induce IL-2, IL-6, IL-10, TNF, IFN-y
specific release
in whole blood from 10 different donors in wet-coated plate or soluble formats
above that
observed for the 1gG4 negative control antibody and/or untreated samples.
[00496] Fe Effector Function Assays
[00497] The potential for A219 to elicit CDC or ADCC was evaluated in vitro.
A219 was
not expected to elicit CDC or ADCC because the antibody was designed to
abolish effector
functions.
[00498] The ability of A219 to elicit CDC or ADCC on target-expressing
recombinant
human HEK293 TL1A cells and on the HEK293 parental cell line (negative control
cell line)
was evaluated. CDC was assessed by culturing the cells after treatment with a
range of
concentrations (0.0031 to 30,000 ng/mL) of A219 in the presence of human
complement and
analyzing the viability of target cells by flow cytometry. ADCC was assessed
by culturing
labeled target cells, after treatment with a range of concentrations (0.0031
to 30,000 ng/mL)
of A219, with human PBMCs (3 donors). A human IgG4 antibody was used as a
negative
control in both assays.
[00499] Rituxan (anti-CD20 antibody) was used as a positive control in the CDC
assay
with CD20- expressing Raji cells while Darzalex was used in the ADCC assay
with Daudi
target cells.
[00500] A219 treatment did not cause an increase in CDC-mediated cell killing
of
HEK293 TL1A cells or in HEK293 cells as compared to the negative control
antibody.
Rituxan treatment resulted in an expected increase in complement-mediated
lysis of CD20-
expressing Raji cells.
[00501] A219 treatment did not cause an increase in ADCC-mediated cell killing
of
HEK293 TL1A cells or in HEK293 cells as compared to the negative control
antibody.
Darzalex treatment resulted in an expected increase in ADCC cytotoxicity of
Daudi target
cells.
1005021 In conclusion, and as expected, A219 did not elicit CDC or ADCC of
TL1A-
expressing cells in the presence of human complement or PBMCs, respectively.
[00503] Relationship of Findings to Pharmacokinetics
[00504] A219 exposure in monkeys in the 6-week repeat-dose toxicity study, as
defined by
Cmax and AUC, increased with increasing dose over the dose range tested, and
exposure
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increased in an approximately dose-proportional manner. There were no apparent
sex-related
differences in exposure. There was no clear correlation of ADA with changes in
A219
exposure. However, it is likely that ADA led to the more rapid decrease in
A219
concentrations at later timepoints that was observed in some of the animals.
Accumulation of
A219 was observed in monkeys after repeated once weekly administration.
1005051 The threshold of serum exposures associated with A219-related findings
from the
6-week repeat-dose monkey toxicity study is shown in Table 23. Safety margins
at each dose
level are presented based on a comparison of A219 AUC values from the 6-week
repeat-dose
monkey toxicity study in comparison to projected human AUC values at the
proposed clinical
starting dose of 5 mg.
Table 23. Exposure of anti-TL1A associated with findings in a 6-week repeat-
dose toxicity
study in monkeys.
Study Findings Dose AUC0-168h Cmax
Exposurea
(mg/kg/week) (ug*hr/mL) (ug/mL) Margin
Mortality (1 female) 30 61000 743
425
Pcrivascular infiltrates
As above and: 100 205000 2500
1430
Va scular inflammation
As above and: 300 684000 8760
4770
RBC and a lbumin, globulin, increa sed (NOAEL)
spleen weight (females only), glom en.ilopathy
AUC = area under concentration-time curve; RBC = red blood cells; Cmax=Maximum
observed concentration
a Exposure margins (i.e. safety margins) were calculated by dividing AUCo-res
values in the repeat-dose monkey study by the
projected human AUCo-168 value of 143.5 ug*hr/mL at the projected 5 mg human
starting dose.
1005061 Summary of A219 preclinic al studies
1005071 A219 has sub-nanomolar binding affinity to soluble TL1A and nanomolar
affinity
to membrane-associated TL1A. In in vitro studies, A219 blocked TL1A's ability
to bind and
activate its receptor, DR3. In whole blood, A219 inhibited the TL1A-dependent
IFN-7
response following the ex vivo exposure to immune-complex and a combination of
IL-12 and
IL-18. Additionally, A219 was observed to be highly selective for TL1A with no
detectable
binding to related TNF super family members FAS, LIGHT, or TRAIL.
1005081 The potential toxicity of A219 was assessed in a series of
nonclinical in vitro
assays and in vivo studies in cynomolgus monkeys. The monkey was selected as a
pharmacologically relevant nonclinical species because of similar TL1A protein
sequence
homology and nearly equivalent binding affinity of A219 to monkey TL I A, as
compared to
human. A219 is similarly active in monkey and human in vitro cell-based
assays.
1005091 A219 has been engineered to remove the potential for the mAb to induce
an
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immune response. In in vitro assays, A219 treatment did not lead to antibody-
or cell-
mediated cytotoxicity or cytokine release from peripheral blood cells thus
indicating that it
was not provoking an undesired immune response.
[00510] In a tolerability and pharmacokinetic (PK) study, cynomolgus monkeys
(1/sex/group) were administered A219 intravenous (IV) at 30, 100 and 243
mg/kg/week on
Days 1 and 8 and subsequently followed for approximately 11 weeks to assess
systemic
exposure of A219. There were no A219-related clinical observations or changes
in body
weight, clinical chemistry, or hematology parameters. PK measurements
suggested that A219
has along half-life of 5 to 11 days, which is consistent with human IgG1 in
monkeys.
[00511] A GLP study was performed to evaluate the potential toxicity,
including
immunotoxicity, of A219 and associated systemic exposure after six weeks of
once-weekly
dosing (7 total doses) in cynomolgus monkeys. A219 was administered IV (bolus)
to male
and female monkeys (3/sex/group) at doses of 0 (vehicle control), 30, 100, or
300
mg/kg/week. Recovery animals (2/sex/group) were administered 0 or 300
mg/kg/week of
A219. The clinically relevant no observed adverse effect level (NOAEL) in this
study was
determined to be 300 mg/kg/week (the highest dose tested). There were findings
observed
that were secondary to generation of anti-drug antibodies (ADA) in response to
administration of a humanized monoclonal antibody including a single death in
the 30 mg/kg
group and minimal vascular inflammation, which was the only finding that was
considered
adverse. All findings were fully reversible after a 6-week recovery period
except for
perivascular infiltrates, which persisted minimally in only a few tissues at
300 mg/kg/week,
and minimal glomerulopathy noted in one recovery female at 300 mg/kg/week. ADA-
related
findings observed in nonclinical animal toxicity studies with human monoclonal
antibodies
generally are not considered relevant to humans.
[00512] A six-month repeat-dose monkey toxicity study is performed to evaluate
the
potential for chronic dosing in UC and CD.
Example 16: Phase 1 Clinical Trial
1005131 A Phase la clinical trial in normal healthy volunteers has
begun.
1005141 The Phase la clinical trial is a single-center, double-
blind, placebo-controlled
safety, tolerability and PK study in normal healthy volunteers receiving IV
administration of
A219. The single ascending dose (SAD) phase of the trial consist of 8 subjects
(6 active and 2
placebo) per cohort with up to 6 dose levels. The multiple ascending dose
(MAD) phase of
the trial commences after an equal or higher SAD dose has been studied and
acceptable
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safety and tolerability has been observed. The MAD phase consists of 8
subjects (6 active and
2 placebo) per cohort with up to 5 dose levels. The trial evaluates the
safety, tolerability and
pharmacokinetics of single and multiple doses of A219 via IV administration as
well as the
PK of A219 after single and multiple doses in healthy, ambulatory, non-
smoking, male or
female volunteers aged 18 to 60 years. In addition, the trial determines the
effects of A219 on
pharmacodynamic (PD) markers as well as the exposure-response relationship of
A219 on
PD markers. A synopsis of this study is shown in Table 14.
[00515] A Phase 1b/2a randomized placebo-controlled clinical trial
in patients with
moderate-to-severe UC and an open label Phase lb clinical trial in patients
with moderate-to-
severe CD is conducted.
Table 14. Synopsis of Phase 1, Single-Center, Double-Blind, Placebo-
Controlled, Safety and
Pharmacokinetics Study of anti-TL1A antibody in Healthy Volunteers
OBJECTIVE: To assess:
= The safety and tolerability of single and multiple doses of anti-
TL1A antibody following administration.
= The pharmacokinetics (PK) of anti-TL1A antibody after single
and multiple doses.
= The effects of anti-TL1A antibody on tissue and serum
pharmacodynamic (PD) markers.
= The exposure-response relationship of anti-TL1A antibody on
PD markers.
STUDY DESIGN: Single center, double-blind, randomized, placebo-
controlled, single dose
followed by multiple dose study of anti-TL1A antibody.
SAMPLE SIZE:
Single Dose Phase:
= Eight (8) subjects (6 active, 2 placebo) per dose level; up to 6
dose levels
Multiple Dose Phase:
= Eight (8) subjects (6 active, 2 placebo) per dose level; up to 5
dose levels
Subjects who discontinue the study prematurely may be replaced.
SUBJECT TYPE: Healthy, ambulatory, non-smoking, male or female
volunteers aged 18
to 60 years. Female volunteers must be women of non-childbearing
potential.
DOSAGE AND DOSE Single Ascending Dose (SAD) Phase:
PROGRESSION:
= Placebo (matching volume of 0.9% normal saline [NS])
= anti-TL1A antibody:
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Dose Progression: second and higher dosing cohorts to be selected based
on AEs and available PK and PD data
Multiple Ascending Dose (MAD) Phase
= Placebo (matching volume of 0.9% NS)
= anti-TL1A antibody on Day 1/Weeks 0, Day 15/Week 2, and
Day 29/Week 4
= Dosing Progression: second and higher dosing cohorts to be
selected based on AEs and available PK and PD data.
STUDY = Adverse events, physical examinations,
chest x-ray, vital signs,
PARAMETERS: ECGs, clinical laboratory values, and anti-drug
antibody levels in serum
samples.
= Pharmacokinetics: Concentrations of anti-TL1A antibody in
serum samples will be determined by validated LCMS methods.
= Pharmacodynamics: Change from Baseline in serum and tissue
(in the MAD cohorts where sigmoidoscopy will be performed)
= PD markers
INCLUSION Subjects are required to meet the following
criteria in order to be
CRITERIA: included in the study:
1. Male or female (of non-childbearing
potential only) between 18
and 60 years of age.
2. Females must be of non-childbearing
potential and must have
undergone one of the following sterilization procedures, and have
official documentation, at least 6 months prior to the first dose:
a. hysteroscopic sterilization;
b. bilateral tubal ligation or bilateral salpingectomy;
c. hysterectomy;
d. bilateral oophorectomy, or;
e. be postmenopausal with amenorrhea for at least 1 year prior to
the first dose and have FSH serum levels consistent with
postmenopausal status as per investigator judgment.
Note: A female of non-childbearing potential who has undergone one of
the sterilization procedures mentioned above, but could not provide
official documentation, must be sexually inactive and remain inactive
throughout the study, or must agree to use a physical (e.g., condom,
diaphragm) and a chemical (e.g., spermicide) barrier method from the
time of screening and throughout the study.
3. Male subjects must use reliable forms of
contraception from
screening to 30 days after the end of dosing.
Note: A non-vasectomized, male subject must agree to use a condom
with spermicide or abstain from sexual intercourse during the study until
30 days beyond the last dose of study drug. (No restrictions are required
for a vasectomized male provided his vasectomy has been performed 4
months or more prior to the first dose. A male who has been
vasectomized less than 4 months prior to the first dose, or could not
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provide official documentation, must follow the same restrictions as a
non-vasectomized male).
4. Continuous non-smoker who has not used tobacco or nicotine-
containing products for at least 6 months prior to the first dose of study
drug
5. Good general health as determined by medical history, and by
results of physical examination, chest x-ray, vital signs, ECG, and
clinical laboratory tests obtained within 28 days (4 weeks) prior to study
drug administration.
6. Subjects must have documentation of positive serology for
varicella zoster virus (VZV) immunoglobulin G (IgG) antibody status.
7. Able to provide written informed consent and understand and
comply with the requirements of the study.
EXCLUSION Subjects with the following characteristics will
be excluded from the
CRITERIA: study:
1. Subject participation in more than one cohort.
2. History or presence of any clinically significant organ system
disease that could interfere with the objectives of the study or the safety
of the subjects.
3, Blood pressure and heart rate are outside
the ranges 90-140
mmHg systolic, 40-90 mmHg diastolic, heart rate 60-100 beats/min.
4. 12-lead ECG with any abnormality judged by the Investigator to
be clinically significant, QRS 110 milliseconds (msec), or QT/QTcF
interval of > 450 msec for men or >470 msec for women.
5. Presence or history of any abnormality or illness, which in the
opinion of the Investigator may affect absorption, distribution,
metabolism or elimination of the study drug.
6. Any screening laboratory evaluation outside the laboratory
reference range that is judged by the Investigator to be clinically
significant.
7. History of or current active tuberculosis (TB) infection; history
of latent TB that has not been fully treated or current latent TB infection.
8. History of more than one episode of herpes zoster infection or
history of disseminated herpes zoster infection.
9. Positive serum test for HIV, hepatitis C or hepatitis B virus
infection.
10. History of significant allergy to any medication.
11. History of alcohol or drug abuse within the past 24 months.
12. Administration of any prescription drug within 21 days of study
drug administration; or over-the-counter drug (acetaminophen and
ibuprofen < 1 g/day permitted) or herbal, nutritional or vitamin
supplement within 7 days of study drug administration.
13. Evidence of drug abuse on urine testing, or a positive test for
alcohol.
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14. Administration or use of any investigational drug or device
within 30 days of study drug administration.
15. Blood or plasma donation within 60 days prior to dosing.
1005161 Based on the clinical data from SAD cohorts 5,25, 100, 300, and 600 mg
and
MAD cohort 50 mg, A219 PK exhibits target-mediated drug disposition (TMDD) at
lower
doses and linear PK at higher dose levels after the saturation of the target-
mediated route of
clearance.
1005171 Following a single IV dose of A219, median time to maximum
concentration
(Tmax) values ranged from 1.02 to 1.50 hours postdose. Exposure based on mean
Cmax and
AUCot increased in a greater than dose-proportional manner between the 5,25,
and 100 mg
dose levels and in an approximately dose-proportional manner between the 100,
300, and 600
mg dose levels. After repeat once every other week dosing of 50 mg A219,
exposure was
increased relative to Day 1. Mean C. and AUCo-336hr was approximately 1.3
times higher on
Days 15 and 29 compared to Day 1.
Example 17: Human dosing range and safety margins
1005181 A219 is a humanized monoclonal antibody that binds human TL1A. It is
expected
that the ultimate goal of A219 treatment in humans will be to saturate the TL
target in
disease patients to obtain optimal efficacy. A minimum anticipated biological
effect level
(MABEL) approach is not considered appropriate because A219 is an antagonist
rather than
an agonist antibody, and the safety of antagonizing the TL1A pathway has
already been
established in the clinic. The maximum recommended starting dose for A219 was
chosen
based on the predicted pharmacologically active dose (PAD). A219 does not
cross-react with
murine TL1A but binds with approximately equivalent potency to cynomolgus
monkey
TL1A. Therefore, cynomolgus monkey was considered the relevant species for
scaling
nonclinical A219 pharmacokinetics (PK) to human. Additionally, PK data in the
monkey
suggest that A219 exhibits target mediated drug disposition, which leads to
nonlinear PK in
the dose range where the target is not saturated and linear PK in the dose
range where the
target is saturated.
1005191 The nonclinical PK and TK of A219 were characterized in the monkey and
support the proposed once every other week dosing regimen in humans. Estimated
safety
margins for the starting dose of 5 mg and the highest proposed dose for study,
1000 mg,
relative to the GLP safety data from monkeys are shown in Table 24. This table
compares the
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safety margins derived from various approaches.
Table 24. Predicted safety margins for the starting dose and maximum dose
Predicted Safety Margin Based on a NOAEL in Monkeys of 300 mg/kga
Basis for Calculation 5 mg 1000 mg
Dose 4200 21.0
Cmax 4920 22.9
AUCO-168hr 4770 13.5
Cmax = maximum ob served wncentration; AUCo-loishi= axit under the
wncentrationversus time curve from time to 168 tir postdose
a
Predicted human Cmax values for the 5 and 1000 mg doses are approximately
1.78 and 382 itg/mL, respectively; predicted
human AUCo-iiishi values for the 5 and 1000 nig doses are approximately 143.5
and 50700 lir* itg/mL, respectively . Human
exposure parameter values are based on an assumed body weight of 70 kg.
Example 18: Treatment of IBD with anti-TL1A
1005201 Subjects having inflammatory bowel disease are treated with the anti -
TL1A
antibody A219 using one of the two induction methods of this example:
1005211 Induction method 1: subcutaneous administration of 800 mg of anti-TL1A
on day
1, then weekly at 175-200 mg anti-TL1A for 12 total weeks.
1005221 Induction method 2: intravenous administration of 500 mg of anti-TL1A
every
other week for 12 weeks.
1005231
After the induction period, if the subject is responsive to treatment,
the subj ect is
further treated in a maintenance phase. The maintenance phase comprises
administering 175-
200 mg of anti-TL1A every 2 or 4 weeks.
Example 19: Anti-TL1A antibody binding to both TL1A monomer and TL1A trimer
1005241 To demonstrate that the exemplary anti-TL1A antibody A219 binds to
both TL1A
monomer and TL1A trimer, a peak shifting assay with size exclusion
chromatography was
performed. Briefly, recombinantly produced human TL1A (rhTL1A) was labeled
with Alexa
fluor 488 (AF488) and spiked into normal human serum (NHS). The labeled rhTL1A
in
serum was then injected into a size exclusion column and eluted by monitoring
the AF488
fluorescent signal.
1005251 RhTLIA was observed in at least two peaks for two distinct quaternary
structures,
one for non-covalent trimers and one for monomers (FIG. 9A). The results show
that a
control reference antibody only bound to the trimeric TL1A (FIG. 9B), as only
the trimer
TL1A peak shifted in the presence of the control reference antibody (control
reference
antibody sequence, light chain SEQ ID NO: 382 and heavy chain SEQ ID NO: 383).
In
contrast, A219 bound both TL1A trimers and monomers (FIG. 9C), as both the
monomer and
trimer TL1A peaks shifted in the presence of A219. The results demonstrate
that the
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exemplary anti-TL1A antibody A219 binds to both TL1A monomer and TL1A trimer.
Example 20: PK/PD Models for Determining Effective Dose
[00526] To demonstrate using PK/PD models for determining the effective dose,
an
integrated whole-body physiologically based pharmacokinetic (PBPK) was
established, as
shown in FIG. 10A. The integrated whole body PBPK included a tissue-level
diagram, as
shown in FIG. 10B, to characterize the PK of mAb, ligand, and complex between
mAb and
ligand. The integrated whole-body PBPK model included the following drug-
specific
parameters and/or input: (i) soluble TLIA (sTL I A) is synthesized by immune
cells (e.g.,
dendritic cells) all over the body; (ii) monomeric sTL1A has half-life of 20
minutes, and
trimeric sTL1A has half-life of 1 hour; (iii) affinity parameters (including
the on rate and off
rate) between antibody and sTL1A were fixed to the values measured via SPR
(e.g., as
determined in Example 12); (iv) synthesis rate of sTL1A was adjusted to match
the observed
baseline and PK data; (v) in the diseased individual, the production rate of
sTL1A was
increased by 50-fold in the interstitial space of the intestine. The
parameters and input can be
varied as described herein, including in Section 4.
[00527] The whole-body PBPK model recapitulated the PK observations for A219
and for
TL1A in normal healthy volunteers (NHV). As shown in FIG. 11A, the A219
concentration
predicted by the whole-body PBPK model matched the observed PK for A219 in
NHV.
Furthermore, as shown in FIG. 11B, the TL1A concentration predicted by the
whole-body
PBPK model matched the observed TLIA concentration in NHV during the observed
time
course (assuming constant TL production rate).
[00528] The observed serum concentration of TL1A was almost 10 fold higher
when
A219, an anti-TL1A antibody binding to both monomeric and trimeric TL I A, was
injected,
comparing to that when a control reference antibody that binds to only
trimeric TL1A
antibody was injected in to a subject (FIG. 12A) (control reference antibody
sequence, light
chain SEQ ID NO: 382 and heavy chain SEQ ID NO: 383). Such higher serum TL1A
concentration was recapitulated in the whole-body PBPK, as shown in the curves
in FIG.
12A. Furthermore, the model predicted about 40% monomer TL1A and 60% trimeric
TL I A,
consistent with observations (FIG. 12B). FIG. 12A thus established that
treating patients
with an anti-TL1A antibody that binds to both monomer and trimer TL1 A
sequestered 10
fold higher TL1A into the serum, therefore reduced the TL1A concentration in
diseased
tissues more than an anti-TL1A antibody binding to trimer TL alone. Such
sequestration
of more total TL1A (both monomer and trimer) in serum provides an unexpected
advantage
to a patient who needs to reduce TLIA concentration in diseased tissues, both
in magnitude
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and rate of such TL1A reduction.
1005291 The baseline concentration of TL1A in serum from NHV averaged to about
220
ng/mL (162 to 414 ng/mL, 54 subjects, across ¨110 samples). The baseline
concentration of
TL1A in serum from CD subjects averaged to about 273 (158 to 479 ng/mL, 17 CD
subjects).
Thus the difference of serum TL1A concentration between a NHV and a CD patient
is only
modest, confirming the importance of targeting and reducing the concentration
of soluble
TL1A in the diseased tissue. Assuming all TL1A production come from colon, the
model
determined that a 50 fold over-production in colon would reproduce a serum
concentration of
290 ng/mL TL1A, approximating the observations in UC patient (FIG. 12C). Such
big
difference in TL1A in diseased tissue and the modest corresponding difference
in serum
between NHV and UC patients again highlight the importance of targeting and
reducing the
concentration of soluble TL1A in the diseased tissue.
1005301 To further validate and establish the applicability of the whole-body
PBPK model,
the predicted curves of TL1A concentration in serum of NHVs and UC patients
were
compared with the observations from clinical trials. As shown in FIGS. 13A-
13B, the whole-
body PBPK model consistently predicted the observations of total TL1A serum
concentration
in NHVs and UC patients from reported phase land phase II clinical trials
(Banfield C. et al.,
Br J Clin Pharmacol. 2020 Apr;86(4):812-824; and Danese S et al., Clin
Gastroenterol
Hepatol. 2021 Jun 11; S1542-3565(21)00614-5). As shown in FIG. 13C, the whole-
body
PBPK model also predicted tissue interstitial space TL1A levels in the NHV
(normal tissue
production) and UC patients (50 fold increase in local tissue production) in
the absence of
any administration of anti-TL1A antibodies. Thus the fitness of the whole-body
PBPK model
has been validated by the clinical observations.
1005311 Having established the whole-body PBPK model, the whole-body PBPK
model
was used to simulate the concentration of TL1A in diseased tissues and in
serum with various
scenarios of TL1A over-production in the diseased tissues, in the presence or
absence of
various doses of anti-TL1A A219. As shown in FIGS. 14A-14B, the whole-body
PBPK
model simulated TL concentration in intestine for various level of
TL over-production
in intestine (FIG. 14A) and the corresponding serum (plasma) concentration of
TL1A under
these levels of intestinal TL1A over-production, each in the absence of any
administrations of
any anti-TL1A antibodies.
1005321 When anti-TL1A antibody A219 was injected at various dose, the whole-
body
PBPK model simulated the changes of TL concentration in the diseased tissues
over time
(FIGS. 15A-15U). Such simulation can be plotted against the TL1A concentration
in the
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corresponding tissue or a reference tissue of a NHV to determine whether the
dose is
sufficient to reduce the TL1A concentration in the diseased tissue below the
TL1A
concentration in the corresponding tissue or a reference tissue of a NHV
(FIGS. 15A-15U).
FIGS 15A-15U also depicts such simulation with various parameters of TL1A over-
production in the diseased intestinal tissues (10x, 25x, 50x, or 100x fold
over-production or
fold increase). As shown in FIGS 15A-15U, the higher the fold over-production,
the higher
the dose or more administrations of the anti-TL1A antibody A219 are needed to
reduce and
keep the TL1A concentration in diseased intestinal tissues below that of the
NHV for the
duration indicated in the figures. More specifically, as shown in FIG. 15R,
administration of
500 mg of the anti-TL1A antibody A219 every other week can cover up to about
125 fold
over-production (fold increase) of TL1A in the intestine of a patient. As
shown in FIG. 15S,
administration of a dose at 1000 mg D1, 500 mg W2, W6, W10, (i.e. 100 mg at
day 1, 500
mg at week 2, 500 mg at week 6, and 500 mg at week 10) of the anti-TL1A
antibody A219
can cover up to about 60 fold over-production (fold increase) of TL1A in the
intestine of a
patient. As shown in FIG. 15T, administration of a dose at 1000 mg D1, 500 mg
W4, W8,
W12, (i.e. 1000 mg at day 1,500 mg at week 4,500 mg at week 8, and 500 mg at
week 12)
of the anti-TL1A antibody A219 can cover up to about 55 fold over-production
(fold
increase) of TL1A in the intestine of a patient. As shown in FIG. 15U,
administration of a
dose at 1000 mg D1, 500 mg W2, W4, W8, W12, (i.e. 1000 mg at day 1,500 mg at
week 2,
500 mg at week 4, 500 mg at week 8, and 500 mg at week 12) of the anti-TL1A
antibody
A219 can cover up to about 60 fold over-production (fold increase) of TL1A in
the intestine
of a patient. As shown in FIG. 15V, administration of a dose at 1000 mg D1,
500 mg W2,
W4, W6, W10, (i.e. 1000 mg at day 1, 500 mg at week 2,500 mg at week 4, 500 mg
at week
6, and 500 mg at week 10) of the anti -TL1A antibody A219 can cover up to
about 75 fold
over-production (fold increase) of TL1A in the intestine of a patient.
1005331 For comparison, a reference antibody that only binds to trimeric TL1A
was tested
in the whole-body PBPK model (reference antibody sequence, light chain SEQ ID
NO: 382
and heavy chain SEQ ID NO: 383). As shown in FIG 15W, such reference antibody
failed to
consistently reduce or consistently keep the free TL1A concentration in
diseased tissue of a
patient below the free TL1A concentration in the corresponding tissue of a
normal healthy
volunteer, when the diseased tissue overproduces TL by 50 fold or higher over
the TLIA
production in the corresponding tissue of a normal healthy volunteer. This is
in sharp
contrast with FIG. 15A, in which the anti-TL1A antibody A219 that binds to
both monomeric
TL1A and trimeric TL1A consistently reduced and kept free TL1A concentration
in the
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diseased tissue below the free TLIA concentration in the corresponding tissue
of a normal
healthy volunteer, even if the diseased tissue overproduced TLIA by 100-fold
over the TLIA
production in the corresponding tissue of a normal healthy volunteer. As
described above
and shown in FIGS. 12C, 13C, and 14A-14B, the UC patients were determined to
have a 50-
fold overproduction of TLIA in the diseased tissue to recapitulate the
observed modest
increase in serum TL1A concentration. As such, an anti-TL1A antibody that
binds to both
monomeric and trimeric TL1A reduces the free TL1A concentration in the
diseased tissue of
a patient below the free TL1A concentration in the corresponding tissue of a
normal healthy
volunteer.
[00534] To further demonstrate the advantage of the anti-TL1A antibody that
binds to both
monomeric and trimeric TLIA in treating patients and reducing free TL1A
concentration in
diseased tissues, such antibodies were directly compared with a reference
antibody that only
binds to trimeric TLIA. As shown in FIGS. 15X-15Z, the anti-TL I A antibody
A219 that
binds to both monomeric and trimeric TLIA consistently and significantly
reduced the free
TLIA concentration in the diseased tissue b elow the free TLIA concentration
in the diseased
tissue resulted from the treatment of the reference anti-TL1A antibody that
binds to only
trimeric TLIA (reference antibody sequence, light chain SEQ ID NO: 382 and
heavy chain
SEQ ID NO: 383).
Example 21: Population PK (popPK) Models for Determining the Effective Dose
[00535] Additionally, based on the available PK data available from Example
16, a
population PK model was built to accurately simulate and predict A219 PK in
the population of
normal healthy volunteers. The available PK data were best described by a 2-
compartment model
with linear elimination. Demographic variables (including sex, age, race, and
body size related
variables) and laboratory clinical variables (including hematological, urine,
and chemical
variables) were tested for inclusion in the model for effect on the clearance
and the volume of
distribution in the central compartment. None of these variables were
identified as significant
covariates on the 2 PK parameters evaluated. The population PK parameter
estimates, and
standard error (SE) are described in Table 27. Residual variability of A219
concentrations
associated with the population PK model was 11.9%. Goodness of fit plots are
presented in
FIGS. 16A-16H. These plots indicated good correlations between population
predicted A219
concentrations ("Predicted DV") and observed A219 concentrations ("Observed
DV"), and
between individual predicted A219 concentrations ("IPRED DV") and Observed DV.
No bias in
standardized weighted residuals versus predicted concentrations or versus time
was noted.
Evaluation of the visual predictive check (FIG. 17A) indicated that the
population PK model
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could adequately predict the observed A219 concentrations and was suitable to
be used to
simulate A219 concentrations.
Table 27. PK Parameter Estimates of the Population PK Model of A219
Parameters I Estimates I SE (%)
PKParameters
CL (L/Day) 0.156 15.2
VI (L) 3.62 8.6
V2 (L) 2 0
Q (L/Day) 0.149 7.6
Inter-Individual Variability (%CV)
CL 39.75 54.6
V1 11.03 44.6
V2 0 FIXED
0 FIXED
Residual error
RV(%) I 11.9 I 8.2
1905361 Having established a popPK model, the popPK was used to select an
induction
dose to rapidly achieve steady state concentration. As shown in FIG. 17B, the
loading dose
of the induction regimen of 1000 mg at day 1, 500 mg at week 2, 500 mg at week
6, and 500
mg at week 10 ensures achievement of induction steady state concentration from
day 1.
Furthermore, as shown above in the whole-body PBPK, such an induction regimen
can
address over 100x over-production of TL1A in the colon within the first 5
weeks of induction
and over 60x over-production for the 12 week period.
Example 22: A Phase 2, Multi-Center, Double-Blind, Placebo-Controlled Study to
Evaluate the Safety, Efficacy, and Pharmacokinetics of Induction Therapy with
A219 in
Subjects with Moderately to Severely Active Ulcerative Colitis.
1005371 To validate the efficacy of the anti-TL1A antibody A219 in ulcerative
colitis
(UC), a phase 2 clinical trial is conducted. The clinical trial includes an
induction period, as
shown in FIG. 18A, and an open-label extension (maintenance) period, as shown
in FIG.
18B. The detailed design of the clinical trial protocol is shown in the
protocol synopsis of
Table 28 below. The disclosure provides that clearance of free soluble TL1A
(sTL1A) from
the gut will translate into efficacy. Therefore, a physiologically based PK
model (as
described in Example 20) was used to predict the impact of various dosing
regimen of A219
on the level of sTL1A in normal and disease states in the central compartment
(serum) and
gut. The model predicts that the proposed induction regimen will lead to sTL1A
levels of
lower than healthy volunteers if the over-production level of sTL1A in the
colon is as high as
60-fold. After the 12-week induction, subjects who are in response will
continue in the open-
label extension randomized to 2 maintenance regimens. The maintenance regimen
of 250 mg
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Q4W is selected to maintain the sTL1A level to below that of healthy
volunteers if the
production of sTL1A in the colon is up to 20 x and the 100 mg Q4W regimen is
selected to
maintain the sTL1A level to below that of healthy volunteers if the production
of sTL1A in
the colon is up to 10'.
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Table 28. PROTOCOL SYNOPSIS
TITLE: A Phase 2, Multi-Center, Double-Blind,
Placebo-Controlled Study to Evaluate
the Safety, Efficacy, and Pharmacokinetics of Induction Therapy with
A219 in Subjects with Moderately to Severely Active Ulcerative Colitis
PROJECT PHASE: Phase 2
OBJECTIVE: Primary:
= To assess the safety and tolerability of A219 following 12-weeks of
induction therapy
= To compare the efficacy of A219 vs placebo for induction of clinical
remission at Week 12
Secondary:
All objectives below refer to comparison of A219-treated subjects vs
placebo-treated subjects in Cohort 1. For the objectives where the
companion diagnostic (CDx) status is a variable, a comparison of subjects
in both Cohort 1 and Cohort 2 will be conducted.
= To compare the efficacy of A219 vs placebo for induction of
endoscopic improvement at Week 12
= To compare the efficacy of A219 vs placebo for induction of clinical
response at Week 12
= To compare the efficacy of A219 vs placebo in CDx positive
(CDx+) subjects (Cohort 1 + Cohort 2) for induction of clinical
remission at Week 12
= To compare the efficacy of A219 vs placebo for induction of
histologic remission at Week 12
= To compare the efficacy of A219 vs placebo for induction of
histologic-endoscopic mucosal improvement at Week 12
= To compare the efficacy of A219 vs placebo in CDx+ subjects
(Cohort I + Cohort 2) for induction of endoscopic improvement at
Week 12
= To compare the efficacy of A219 vs placebo in CDx+ subjects
(Cohort 1 + Cohort 2) for induction of clinical response at Week 12
= To compare the efficacy of A219 vs placebo in CDx+ subjects (Cohort
1 + Cohort 2) for induction of histologic remission at Week 12
= To compare the efficacy of A219 vs placebo in CDx-F subjects
(Cohort 1 + Cohort 2) for induction of histologic -endoscopic mucosal
improvement at Week 12
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= To compare the efficacy of A219 in CDx+ (Cohort 1 + Cohort 2) vs
CDx negative (CDx-) subjects for induction of clinical remission at Week
12
= To compare the efficacy of A219 vs placebo for induction of
mucosal healing at Week 12
= To compare the efficacy of A219 vs placebo in CDx+ subjects
(Cohort 1 + Cohort 2) for induction of mucosal healing at Week 12
= To compare the efficacy of A219 vs placebo for change in
Inflammatory Bowel Disease Questionnaire (I BDQ) at Week 12
= To compare the efficacy of A219 vs placebo in CDx+ subjects
(Cohort 1 + Cohort 2) for change in IBDQ at Week 12
= To compare the efficacy of A219 vs. placebo in subjects who are
CDx+ per alternative algorithm (Cohort 1 + Cohort 2) for clinical
remission at Week 12
Exploratory:
= To assess the pharmacokinetics (PK) of A219 in subjects with
ulcerative colitis (UC) over time
= To assess the effects of A219 on tissue and serum pharmacodynamic
(PD) markers, including total TL1A concentrations over time
= To assess the effect of A219 on inflammatory biomarkers including
fecal calprotectin and high sensitivity C-reactive protein (hsCRP) overtime
= To assess the proportion of subjects in 3-component Modified Mayo
Score response, 3-component Modified Mayo Score remission,
endoscopic improvement, Robarts histopathology index (RHI) histologic
remission, Geboes score histologic remission, and mucosal healing at
Week 50
= To assess the change in Partial Mayo Score over time
= To assess the change in Geboes Index and RHI from Baseline to
Week 12 and Week 50
= To assess the exposure-response relationship of A219 on PD markers
over time
= To assess the proportion of subjects achieving corticosteroid-free-
remission at Week 50
STUDY DESIGN: This is a multi-center, double-blind,
randomized, placebo-controlled proof
of concept study designed to assess the safety, tolerability, and efficacy of
A219 following 12 weeks of induction therapy in subjects with UC. This
study will be conducted under the aegis of a Data Monitoring Committee
(DMC) and will commence following the demonstration of an acceptable
safety profile of A219 at a dose of > 500 mg in the multiple ascending dose
study in normal healthy volunteers (Example 16).
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The study has 4 periods (Screening Period, Induction Period [IP], Open-
Label Extension [OLE] Period, and Follow-Up [FU] Period). The study will
have 2 Cohorts that will enroll subjects in a sequential fashion utilizing an
adaptive design as described below.
Cohort 1: Following the Screening Period, approximately 120 eligible
subjects with moderately to severely active UC will enter the IP and be
randomized in a 1:1 fashion to receive intravenous (IV) administration of
A219 1000 mg on Week 0/Day 1, followed by 500 mg on Weeks 2, 6, and
10, or placebo at the same timepoints. Randomization will be stratified by
CDx status of positive (CDx+) or negative (CDx-) and prior biologic
experience (yes/no) at Week 0/Day 1. Subjects who discontinue from the
study will have a follow-up period of 12 weeks after last dose.
Cohort 2: When approximately 80% of Cohort 1 subjects (i.e., ¨96 subjects)
have reached Week 12 or early terminated from the study, the DMC will
conduct an unblinded analysis of clinical efficacy in CDx+ subjects and will
recommend whether an expansion to Cohort 2 is warranted. The planned
sample size for CDx+ subjects (combining Cohort 1 and Cohort 2) will be
approximately 40, in the case where Cohort 2 is initiated. For Cohort 2,
eligible subjects (who must be CDx+) will enter the IP and be randomized
in a 1:1 fashion to receive IV administration of A219 1000 mg on
Week 0/Day 1, followed by 500 mg on Weeks 2, 6, and 10, or placebo at
the same timepoints. Randomization will be stratified by prior biologic
experience (yes/no) at Baseline. Subjects who discontinue from the study
will have a follow-up period of 12 weeks after last dose.
Subjects who complete the 12-week IP from either Cohort will have the
option to enter OLE. During OLE, starting at Week 14 visit:
= Subjects who have achieved deep remission (defined as in clinical
remission [endoscopic subscore of 0 or 1, rectal bleeding subscore of 0, and
stool frequency subscore of 0 or 1 and not greater than Baseline] and RHI <
3) will continue in the study and have therapy withdrawal.
o Upon disease relapse (defined as rectal
bleeding score of >I, and either
hsCRP > 5 and/or fecal calprotectin > 250), subjects can receive another
course of induction therapy (1000 mg IV followed by 500 mg IV 2, 6, and
weeks after the first infusion) followed by maintenance therapy of 250
mg IV every 4 weeks (Q4W) for atotal of 50 weeks.
= Responders (defined as reduction from Baseline > 2 points and > 30%
in 3-component Modified Mayo Score, accompanied by a reduction > lin
rectal bleeding subscore or absolute rectal bleeding subscore < 1) who have
not achieved deep remission will be re-randomized, stratifiedby CDx status
of CDx+ or CDx-, to either 250 mg IV Q4W or 100 mg IV Q4W, starting at
Week 14 until Week 50.
= Nonresponders will receive an open-label induction regimen of
1000 mg of A219 on Week 14, followed by 500 mg on Weeks 16,20, and
24. Nonresponders who do not respond at Week 28 (per investigator
discretion) should be discontinued from the study.
Nonresponders who respond at Week 28 (per investigator discretion)
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will be re-randomized to either 250 mg IV Q4W or 100 mg IV Q4W,
starting at Week 28 for a total of 50 weeks.
The study may be amended by the Sponsor to extend the OLE period
beyond 50 weeks based on emerging safety data.
The study also includes an optional PK sub-study during the IP for subjects
who consent to additional PK sampling.
SAMPLE SIZE: The study is planned to randomize up to
approximately 170 subjects,
approximately 120 in Cohort 1 and up to 50 in Cohort 2. A sample size of
60 per arm in Cohort 1 will enable a statistical power of > 80% for the
primary endpoint at 1-sided significance level of 0.025 using Cochran-
Mantel-Haenszel (CMH), assuming clinical remission rate of 5% for
placebo and 24% for A219. Additionally, the sample size will confer
> 80% power to achieve statistical significance for the 1st secondary
endpoint of endoscopic improvement with an overall 1-sided alpha level of
0.025, assuming the endoscopic improvement rates are 15% and 38% for
placebo and A219 groups, respectively.
Additionally, for analyses of the CDx population (combining CDx+
subjects from Cohort 1 and Cohort 2), a sample size of 40 per arm will
provide a statistical power of? 80% at a 1-sided alpha level of 0.025,
according to a group sequential design with anon-binding futility interim
analysis when 18 subjects per arm reach Week 12, assuming clinical
remission rate of 5% for placebo and 31% for A219.
SUBJECT TYPE: Male or female subjects? 18 years of age with
moderately to severely
active UC.
FORMULATIONS: A219 will be supplied in 10 mL vials each
containing 500 mg A219(60
mg/mL solution) for IV administration after reconstitution.
DOSAGE: Subjects will be stratified by CDx+/CDx-
status and prior biologic
experience (yes/no) in a 1:1 ratio to:
= A219 1000 mg IV on Week 0/Day 1, followed by 500 mg IV on
Weeks 2, 6, and 10
= Placebo IV on Week 0/Day 1, followed by placebo IV on Weeks 2, 6,
and 10
During OLE:
= Deep remitters will enter the therapy withdrawal period
o All subjects who develop disease relapse after therapy withdrawal will
receive another course of induction therapy (1000 mg IV followed by 500
mg IV 2, 6, and 10 weeks after the first infusion) followedby maintenance
therapy of 25() mg IV Q4W fora total of50weeks.
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= Responders at the end of Week 12 will be stratified by CDx status of
CDx+ or CDx- and re-randomized to receive one of the following
regimens:
o A219 250 mg IV on Week 14 then Q4W until Week 50
o A219 100 mg IV on Week 14 then Q4W until Week 50
= Nonresponders at the end of Week 12 will receive open-label A219
1000 mg IV on Week 14, followed by A219 500 mg IV on Weeks 16, 20,
and 24. Subjects who do not respond by Week 26 should be discontinued
from the study. Subjects who respond by Week 26 will be stratified by CDx
status of CDx+ or CDx- and re-randomized to receive one of the following
regimens:
o A219 250 mg IV on Week 28 then Q4W for a total of 50 weeks
o A219 100 mg IV on Week 28 then Q4W for a total of 50 weeks
ROUTE OF All study drug will be reconstituted in 250
mL of 0.9% normal saline (NS)
ADMINISTRATION: and will be administered IV over 30 minutes.
STUDY ENDPOINTS: Primary endpoints:
= The proportion of subjects reporting adverse events (AEs), serious
adverse events (SAEs), AEs leading to discontinuation, and markedly
abnormal laboratory values.
= The proportion of subjects in the 3-component Modified Mayo Score
clinical remission (as defined by endoscopic subscore of 0 or 1, rectal
bleeding subscore of 0, and stool frequency subscore of 0 or 1 and not
greater than Baseline) at Week 12. The 3-component Modified Mayo Score
ranges from 0-9 and includes rectal bleeding, stool frequency and
endoscopic assessment domains.
Secondary endpoints:
= The proportion of subjects with endoscopic improvement, as defined by
endoscopy subscore < 1 with no friability) at Week 12.
= The proportion of subjects in 3-component Modified Mayo Score clinical
response at Week 12. The 3-component Modified Mayo Score clinical
response is defined by reduction from Baseline > 2 points and > 30% in 3-
component Modified Mayo Score, accompanied by a reduction?: 1 in rectal
bleeding subscore or absolute rectal bleeding subscore < 1.
= The proportion of subjects in the 3-component Modified Mayo Score
clinical remission (as defined by endoscopic subscore of 0 or 1, rectal
bleeding subscore of 0, and stool frequency subscore of 0 or 1 and not greater
than Baseline), in CDx+ subjects (Cohort 1 + Cohort 2) treated with A219
compared to CDx+ placebo-treated subjects at Week 12. The 3-component
Modified Mayo Score ranges from 0-9 and includes rectal bleeding, stool
frequency, and endoscopic assessment domains.
= The proportion of subjects with histologic remission (defined Geboes
score < 3.1) at Week 12.
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= The proportion of subjects with histologic-endoscopic mucosal
improvement (defined as Geboes score < 3.1 and endoscopy subscore
< 1 with no friability) at Week 12.
= The proportion of subjects with endoscopic improvement, as defined by
endoscopy subscore < 1 with no friability, in CDx+ subjects (Cohort 1
+ Cohort 2) treated with A219 compared to CDx+ placebo-treated subjects
at Week 12.
= The proportion of subjects in 3-component Modified Mayo Score
clinical response in CDx+ subjects treated with A219 compared to CDx+
placebo-treated subjects at Week 12. The 3-component Modified Mayo
Score clinical response is defined by reduction from Baseline > 2points and
> 30% in 3-component Modified Mayo Score, accompanied by a reduction
> 1 in rectal bleeding subscore or absolute rectal bleeding subscore < 1.
= The proportion of subjects with histologic remission, defined as Geboes
score <3.1, in CDx+ subjects (Cohort 1 + Cohort 2) treated with A219
compared to CDx+ placebo-treated subjects at Week 12.
= The proportion of subjects with histologic-endoscopic mucosal
improvement (defined as Geboes score < 3.1 and endoscopy subscore
< 1 with no friability), in CDx+ subjects (Cohort 1 + Cohort 2) treated
with
A219 compared to CDx+ placebo-treated subjects at Week 12.
= The proportion of subjects with clinical remission (defined as
endoscopic subscore of 0 or 1, rectal bleeding subscore of 0, and stool
frequency subscore of 0 or 1 and not greater than Baseline) in CDx+
subjects (Cohort 1 + Cohort 2) treated with A219 compared to in CDx-
subjects treated with A219 at Week 12.
= The proportion of subjects with mucosal healing (defined as Geboes
score < 2B.1 and endoscopy subscore of < 1) at Week 12.
= The proportion of subjects with mucosal healing (defined as Geboes
score < 2B.1 and endoscopy subscore of < 1), in CDx+ subjects (Cohort
1 + Cohort 2) treated with A219 compared to CDx+ placebo-treated
subjects at Week 12.
= The proportion of subjects with IBDQ response, as defmed by? 16-
point increase from Baseline at Week 12.
= The proportion of subjects with IBDQ response, as defined by > 16-
point increase from Baseline, in CDx+ subjects (Cohort 1 + Cohort 2)
treated with A219 compared to CDx+ placebo-treated subjects at Week
12.
= The proportion of subjects in the 3-component Modified Mayo Score
clinical remission (as defined by endoscopic subscore of 0 or 1, rectal
bleeding subscore of 0, and stool frequency subscore of 0 or 1 and not
greater than Baseline), in CDx+ subjects per alternative algorithm (Cohort
1 + Cohort 2) treated with A219 compared to CDx+
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placebo-treated subjects per alternative algorithm at Week 12. The 3-
component Modified Mayo Score ranges from 0-9 and includes rectal
bleeding, stool frequency, and endoscopic assessment domains.
Exploratory endpoints:
= The pharmacokinetics of A219 in subjects with UC after multiple
doses
= The change from Baseline in serum and fecal inflammatory biomarkers
(PD markers)
= The proportion of subjects in 3-component Modified Mayo Score
response, 3-component Modified Mayo Score remission, endoscopic
improvement, RHI histologic remission, Geboes score histologic
remission, and mucosal healing at Week 50
= The change in Partial Mayo Score (with or without PGA component)
over time
= The change in Geboes Index and RHI from Baseline to Week 12 and
Week 50
= The exposure-response relationship of A219 on PD markers
= Within subpopulation of subjects on cortico steroid at study entry, the
proportion of subjects in clinical remission and off of corticosteroid at
Week 50
INCLUSION Subjects are required to meet the following
criteria in order to be included in
CRITERIA: the study:
1. Male or female > 18 years of age.
2. Subjects must have had a documented diagnosis of UC (endoscopy +
histology) to be eligible for study participation. For subjects with no
documented confirmation of UC diagnosis or if previous diagnosis isnot
deemed conclusive, UC diagnosis must be confirmed at time of screening
colonoscopy.
3. Moderately to severely active UC as defined by 3-component Modified
Mayo score (3 components of rectal bleeding, stool frequency, and
endoscopy) of 4 to 9, inclusive, with Modified Mayo endoscopic subscore >
2 and rectal bleeding sub score > 1.
4. Subjects must satisfy at least one of the following criteria:
a) In the past, had an inadequate
response to one or more of the
following treatments:
= Oral prednisone > 40 mg/day (or equivalent) or budesonide > 9
mg/day or equivalent or beclomethasone > 5 mg/day for at least 2 weeks
= Corticosteroid dependence as defined by failed to successfully
taper to < 10 mg/day of prednisone or equivalent (i.e., had a
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flare of disease) within 3 months of starting therapy, or if relapse
occurs within 3 months of stopping corticosteroids
= Immunosuppressants (azathioprine > 2 mg/kg/day or
6-mercaptopurine > 1.0 mg/kg/day [or documentation of a therapeutic
concentration of 6-thioguanine nucleotide]) for atleast 8 weeks
= An approved anti-TNF agent at an approved labeled dose for at
least 8 weeks
= Vedolizumab at the approved labelled dose for at least 8 weeks
= An approved JAK inhibitor (e.g., tofacitinib) at an approved
labelled dose for at least 8 weeks
= An approved anti-IL-12/23 (e.g., ustekinumab) at an approved
labelled dose for at least 8 weeks
= An approved sphingosine 1-phosphate receptor (Si PR)
modulator at an approved labelled dose for least 12 weeks
OR
b) Had been intolerant to one or more_of the above-mentioned
treatments (e.g., unable to achieve doses or treatment durations because
of dose limiting side effects [e.g., leukopenia, psychosis, uncontrolled
diabetes, elevated liver enzymes]).
OR
c) Currently receiving one or more of the following treatments:
= Oral Prednisone 10 mg/day (or equivalent) for at least 3 months
= Immunosuppressants [azathioprine > 2 mg/kg/day or
6-mercaptopurine 1.0 mg/kg/day (or documentation of a therapeutic
concentration of 6-thioguaninc nucleotide)] for aticast 8 weeks.
Notes on subjects who have had prior biologic/biologic-like therapy(ies)
(anti-TNF, JAK inhibitor, Si PR modulator, anti-IL-12/23,and/or
vedolizumab):
= The study will include a maximum of 70% subjects who have had
prior biologic/biologic-like therapy(ies) experience. Upon reachingthe
maximum number of allowed biologic/biologic-like experienced subjects
(70%), subjects who have had prior biologic/biologic-like experience will
no longer be allowed to enterthe study.
= Subject cannot have failed (no response, insufficient response, loss
of response, and/or intolerance) > 3 classes or > 4 individual
biologic/biologic-like therapies (refer to exclusion criterion #26).
5. For subjects who are women of childbearing potential (WOCBP)
involved in any sexual intercourse that could lead to pregnancy, the
subject has used two highly effective methods of contraception for at least
4 weeks prior to Day 1 and agrees to continue to use two highly
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effective methods of contraception until at least 12 weeks after the last dose
of study drug.
6. Male subjects must use, with their female
partner of childbearing
potential, two highly effective methods of contraception and refrain from
sperm donation from screening to 12 weeks after the last dose of study
drug.
7. Subject must meet drug stabilization
requirements, as applicable:
a) Oral corticosteroid treatment must be equivalent of < 20 mg
prednisone or < 9 mg budesonide or beclomethasone < 5 mg daily at a
stable dose for at least 2 weeks prior to randomization
b) Oral am inosal icylates should be at a stable dose for at least 2 weeks
prior to randomization
c) Azathioprine and 6-mercaptopurine should be at a stable dose for at
least 4 weeks prior to randomization
8. Able to provide written informed consent
and understand and comply
with the requirements of the study.
9. For Cohort 2 only: Subjects must be CDx+.
EXCLUSION Subjects with the following characteristics
will be excluded from the study:
CRITERIA:
Sex and Reproductive Status
1. WOCBP and men with female partners of childbearing potential who
are unwilling or unable to use two highly effective methods of
contraception to avoid pregnancy for the entire study period and for up to
12 weeks after the last dose of study drug.
2. Women who are pregnant or breastfeeding.
3. Women with a positive pregnancy test on enrollment or prior to
randomization.
Target Disease Exceptions
4. Diagnosis of Crohn's disease or indeterminate colitis.
5. UC limited to the rectum (< 15 cm from anal verge).
6. Current evidence of fulminant colitis, toxic megacolon, or bowel
perforation.
7. Current or impending need for colostomy or ileostomy.
8. Previous total proctocolectomy or partial colectomy.
9. Surgical bowel resection within 3 months before screening.
10. Concomitant primary sclerosing cholangitis (PSC)
Medical IIistory and Concurrent Diseases
11. Past or current evidence of definite low-grade or high-grade colonic
dysplasia that has not been completely removed.
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12. Subjects who are scheduled or anticipate the need for surgery, aside
from dermatologic procedures.
13. .. Subjects who have a history of clinically significant drug or alcohol
abuse.
14. Concomitant illness that in the opinion of the Investigator, is likely
to
require systemic glucocorticosteroid therapy during the study (e.g.,
moderate to severe asthma).
15. Current symptoms of severe, progressive, or uncontrolled renal,
hepatic, hematological, pulmonary, cardiac, neurological,
ophthalmologic or cerebral disease. Concomitant medical conditionsthat
in the opinion of the Investigator might place the subject at unacceptable
risk for participation in this study.
16. .. Subjects with a history of cancer within the last 5 years (other than
non-melanoma skin cell cancers cured by local resection). Existing non-
melanoma skin cell cancers must be removed prior to enrollment. Subjects
with carcinoma in situ or localized cervical cancer, treated with definitive
surgical intervention, are allowed.
17. Subjects at risk for tuberculosis (TB). Specifically, subjects with:
a) A history of active TB
b) Current clinical, radiographic or laboratory evidence of active TB
c) Latent TB which was not successfully treated. Subjects with a
positive TB screening test indicative of latent TB will not be eligible for
the
study unless active TB infection has been ruled out, and an appropriate
course of intervention for latent TB has been initiated at least 2 weeks prior
to randomization, and no evidence of active TB on chest x-ray during
Screening.
18. Subjects with any serious bacterial infection within the last 3 months,
unless treated and resolved with antibiotics, or any chronic bacterial
infection (such as chronic pyelonephritis, osteomyelitis and
bronchiectasis).
19. Female subjects who have had a breast cancer screening that is
suspicious for malignancy, and in whom the possibility of malignancy
cannot be reasonably excluded following additional clinical, laboratoryor
other diagnostic evaluations.
20. Subjects with any active infections (excluding fungal infections of
nail
beds) including, but not limited to, those that require intravenous (IV)
antimicrobial treatment 4 weeks or oral antimicrobial treatment 2 weeks
prior to randomization. Subjects with evidence of Human
Immunodeficiency Virus (HIV), Hepatitis B or Hepatitis C infection
detected during screening are also excluded, but subjects with successfully
treated Hepatitis C with no recurrence for? 1 year are allowed. Subjects
with active documented or suspected COVID-19
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infection within 4 weeks of randomization or asymptomatic SARS -CoV-
2 PCR test within 2 weeks of randomization are excluded.
21. Subjects with herpes zoster reactivation or cytomegalovirus (CMV)
that resolved less than 2 months prior to signing informed consent.
22. Subjects who have received any live
vaccines within 3 months of the
anticipated first dose of study medication or who will have need of alive
vaccine at any time during the study.
Physical and Laboratory Test Findings
23. Positive stool Polymerase Chain Reaction (PCR) or culture for enteric
pathogens.
24. Stool positive for Clostridium difficile
(C. difficile) toxin. Subjects who
are positive can be retested after the completion of a full course of
treatment for C. difficde infection.
25. Any of the following lab values:
a) Hemoglobin (Hgb) < 8.0 g/dL (80 g/L)
b) White blood cell (WBC) < 2,500/mm3 (2.5 x 109/L)
e) Neutrophils < 1,000/mm3 (1 x 109/L)
d) Platelets < 100,000/mm3 (100 x 109/L)
e) Serum creatinine > 2 times upper limit of normal (ULN)
Serum alanine aminotransferase (ALT) or aspartate
aminotransferase (AST) > 2 times ULN
g) Any other laboratory test results
that, in the opinion of the
Investigator, might place the subject at unacceptable risk for
participation in this study
Prohibited Therapies and/or Medications
26. Failed (no response, insufficient
response, loss of response, and/or
intolerance) > 3 classes (anti-TNF, anti-integrin, anti-IL12/23, JAK
inhibitor, S1PR modulator) or > 4 individual biologic/biologic-like
therapies.
27. Any marketed biologic or biologic-like within 2 weeks for tofacitinib, 8
weeks for anti-INF agents, 10 weeks for S1PR modulators, and 12 weeks
for vcdolizumab and ustckinumab prior to randomization or if drug level per
therapeutic dose monitoring is greater than lower limit ofdetection.
28. Any biologic immunomodulators not covered in exclusion criterion 27,
used for UC or other conditions within 8 weeks or 5 half-lives, whichever is
longer, prior to randomization or if drug level per therapeutic dose
monitoring is greater than lower limit of detection.
29. Rituximab within 1 year prior to randomization.
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30. Parenteral corticosteroids within 4 weeks or rectal administration of
corticosteroids within 2 weeks prior to randomization.
31. Rectal administration of 5-A SA within 2 weeks prior to randomization.
32. Tacrolimus, methotrexate, cyclosporine, mycophenolate mofetil
(CellCeptc), immunoadsorption columns (such as Prosorba columns), D
Penicillamine, Leflunomide, Thalidomide, fish-oil preparations, probiotics,
fecal transplantation, non-steroidal anti-inflammatory agents (NSA1Ds),
aspirin > 81 mg/day within 2 weeks prior to randomization.
33. Other investigational chemical agent within 30 days or other
investigational biologic agent within 8 weeks or 5 half-lives (whicheveris
longer) of randomization.
34. Prior exposure to A219.
Other Exclusion Criteria
35. Prisoners or subjects who are compulsorily detained (involuntarily
incarcerated) for treatment of either a psychiatric or physical (e.g.,
infectious disease) illness must not be enrolled into this study.
36. Legal or mental incapacitation, or inability to understand and comply
with the requirements of the study.
Statistical Methods: Statistical methods will be detailed in the
Statistical Analysis Plan. The
SAP will provide details about the method of analysis and specific planned
analyses, and will be prepared and approved by Prometheus Biosciences
and its designees before study database lock and unblinding of subject
treatment assignments.
The analysis populations are defined as follows:
= Full analysis set (FAS) from Cohort 1: all subjects randomized and
treated in Cohort 1
= FAS for CDx+: all CDx+ subjects who are randomized and treated in
both Cohort 1 and Cohort 2
= Safety analysis set: all subjects treated
The following analyses will be performed:
Efficacy:
The efficacy assessment will test for the difference between A219 and
placebo groups in FAS.
"lhe primary endpoint will be analyzed and compared between A219 and
placebo treatment groups in FAS from Cohort 1. The primary endpoint, the
proportion of subjects achieving clinical remission, will be tested between
the 2 treatment groups at 1-sided significance level of 0.025 using CMH
with stratification factors at randomization. If significant, the lst
secondary
endpoint of proportion of subjects achieving endoscopic improvement will
be tested between the 2 treatment groups at 1-sided significance level of
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0.025. If significant, the 2nd, 3rd, 4th, and 5th secondary endpoints will be
tested sequentially, each at 1-sided significance level of 0.025. Testing for
statistical significance will stop when the first endpoint is not
statistically
significant at level of 0.025 and all remaining p values will be nominal.
Treatment difference for primary and secondary endpoints for Cohort 1 will
be estimated along with 95% CI for all subjects in FAS. The secondary
endpoints in CDx+ subjects will be summarized and compared between
A219 and placebo groups in FAS for CDx-P, while the treatment difference
will be estimated with 95% CI. Additional efficacy analysis will be detailed
in SAP.
Interim Efficacy Analysis:
An interim analysis will be carried out when approximately 80% of
subjects (approximately 96 subjects) in Cohort 1 have reached Week 12 or
early terminated from the study. The DMC will review the unblinded
efficacy and safety data and recommend on the expansion to Cohort 2.
Decision rules to initiate Cohort 2 are determined according to the futility
bounds of group sequential design of a sample size of 40 per arm with one
interim analysis at the information fraction of 45%. Because the exact
bounds will be calculated using the actual number of subjects with CDx+
included in the interim analysis, the final decision rules, along with
sensitivity analysis, will be specified in the DMC SAP, prior to the interim
analysis.
Adverse Events:
AEs will be coded using the most current version of Medical Dictionary for
Regulatory Activities (MedDRA ).
A by-subject AE data listing, including verbatim term, preferred term (PT),
system organ class (SOC), treatment, severity, seriousness criteria,
relationship to drug, and action taken, will be provided.
The number of subjects experiencing treatment-emergent adverse events
(TEAEs) and number of TEAEs will be summarized by treatment using
frequency counts for Safety analysis set.
Medical History, chest x-ray, electrocardiogram (ECG), and physical
examination will be listed by subject.
Changes in ECGs and physical examinations will be described in the text of
the final report.
Concomitant Medications:
Concomitant medications will be coded using the most current World
Health Organization (WHO) drug dictionary and listed by treatment.
Pharmacokinetics:
Summary statistics of A219 concentrations and anti-drug antibody
(ADA) by visit and by CDx+ and CDx-.
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Example 23: A Phase 2a, Multi-Center, Open-Label Study to Evaluate the Safety,
Efficacy, and Pharmacokinetics of A219 in Subjects with Moderately to Severely
Active
Crohn's Disease.
1005381 To validate the efficacy of the anti-TL1A antibody A219 in Crohn's
disease (CD),
a phase 2 clinical trial is conducted. The clinical trial includes an
induction period, as shown
in FIG. 19, and an open-label extension (maintenance) period, also shown in
FIG. 19. The
detailed design of the clinical trial protocol is shown in the protocol
synopsis in Table 29
below. The disclosure provides that clearance of free soluble TL1A (sTL1A)
from the gut
will translate into efficacy. Therefore, a physiologically based PK model (as
described in
Example 20) was used to predict the impact of various dosing regimen of A219
on the level
of sTL1A in normal and disease states in the central compartment (serum) and
gut. The
model predicts that the proposed induction regimen will lead to sTL1A levels
of lower than
healthy volunteers if the over-production level of sTL1A in the colon is as
high as 60-fold.
After the 12-week induction, subjects who are in response will continue in the
open-label
extension randomized to 2 maintenance regimens. The maintenance regimen of 250
mg Q4W
is selected to maintain the sTL1A level to below that of healthy volunteers if
the production
of sTL1A in the colon is up to 20x and the 100 mg Q4W regimen is selected to
maintain the
sTL1A level to below that of healthy volunteers if the production of sTL1A in
the colon is up
to 10x.
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Table 29. PROTOCOL SYNOPSIS
TITLE: A Phase 2a, Multi-Center, Open-Label Study to
Evaluate the Safety,
Efficacy, and Phannacokinetics of A219 in Subjects with Moderately to
Severely Active Crohn' s Disease
PROJECT PHASE: Phase 2a
OBJECTIVE: Primary:
= To evaluate the safety and tolerability of A219 following 12-weeksof
induction therapy
= To assess the proportion of subjects with endoscopic improvement
(decrease in simple endoscopy score for Crohn's disease [SES-CD]
> 50% from Baseline) at Week 12
Secondary:
= To assess the proportion of subjects with clinical remission (Crohn's
disease activity index [CDAI] < 150) at Week 12
= To assess the proportion of subjects with endoscopy and clinical
improvement (decrease in SES-CD > 50% AND reduction in CDAI
> 100 points from Baseline) at Week 12
= To assess the proportion of subjects with biomarker and clinical
improvement (decrease in high sensitivity C-reactive protein [hsCRP] or
fecal calprotectin > 50% from Baseline, among subjects with at least one
elevated biomarker at Baseline, AND reduction in CDAI > 100 points from
Baseline) at Week 12
= To assess the proportion of subjects with normalization of C-reactive
protein (hsCRP < upper limit of normal [ULN]), among subjects with
elevated concentrations at Baseline, at Week 12
= To assess the proportion of subjects with normalization of fecal
calprotectin (fecal calprotectin < ULN), among subjects with elevated
concentrations at Baseline, at Week 12
= To assess the proportion of subjects with clinical improvement
(reduction in CDAI > 100 points from Baseline) at Week 12
= To assess the proportion of subjects with two component patient-
reported outcome (PRO-2) remission (average daily abdominal pain score
< 1 point and average daily stool frequency <3 points with abdominal pain
and stool frequency no worse than Baseline at Week 12)
= To assess the change in SE S-CD score from Baseline to Week 12
= To assess the pharmacokinetics (PK) of A219
= To assess the immunogenicity of A219
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Exploratory:
= To assess the change in CDA1 and component scores over time
= To assess the effects of A219 on tissue and serum pharmacodynamic
(PD) markers, including tumor necrosis factor-like cytokine IA (TL1A)
concentrations, endoscopic healing index (EH1), fecal calprotectin, and
hsCRP in all subjects over time
= To assess the change in SE S-CD at Week 50 from Baseline
= To characterize the change in Perianal Disease Activity Index (PDAI)
score from Baseline to Week 12, Week 28, and Week 50
= To characterize the effect of A219 for improvement and remission of
enterocutaneous and/or perianal fistula during the Induction Period(1P) and
Open-Label Extension (OLE)
= To assess all secondary endpoints at Week 50
= To assess the change in global histological activity score (GHAS) and
Robarts histopathology index (RHI) from Baseline to Week 12 and Week
= To assess the proportion of subjects with histologic response and
histologic remission at Week 12 and Week 50
= To assess change in PRO-2 over time
= To assess change in extraintestinal manifestations over time
STUDY DESIGN: This is a multi-center, open-label, proof of
concept study designed to assess
the safety, tolerability, and preliminary efficacy of A219 following
12 weeks of induction therapy in subjects with Crohn' s disease (CD). This
study will be conducted under the aegis of a Data Monitoring Committee
(DMC) and will commence following the demonstration of an acceptable
safety profile of A219 at a dose of > 500 mg in the multiple ascending dose
study in normal healthy volunteers (Study PR200-101).
The study has 4 periods (Screening, IP, OLE and Follow-Up [FU] Period).
Following the Screening Period, approximately 50 eligible subjects with
moderately to severely active CD will enter the IP to receive A219 1000 mg
on Week 0/Day 1, followed by 500 mg on Weeks 2, 6, and 10 via
intravenous (IV) administration. Subjects who discontinue from the study
will have a follow-up period of 12 weeks after the last dose.
Response at Week 12 will be defined as reduction from Baseline in CDAI
of? 100 points. Non-responders at Week 12 should discontinue from the
study.
Subjects who complete the 12-week IP and have responded will have the
option to enter OLE. Subjects will continue in OLE until they progress,
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withdraw from the study, study termination, or Week 50. During the OLE,
starting at Week 14 visit:
= Subjects who achieved deep remission (defined as clinical remission
with CDAI < 150, endoscopic remission with SES-CD < 4 with none of
the segments with score of more than 1, and RHI < 3) will continue in the
study and have therapy withdrawal
o
Upon disease relapse (defined as CDAI > 220 and either hsCRP
> 5 mg/L and/or fecal calprotectin > 250 g/g), subjects can receive
another course of induction therapy (1000 mg IV followedby 500 mg IV 2,
6, and 10 weeks after the first infusion) followed by maintenance therapy
of 250 mg IV every 4 weeks (Q4W) for atotal of 50 weeks
= Other subjects will be re-randomized to either 250 mg IV Q4W or
100 mg IV Q4W until Week 50
The study may be amended by the Sponsor to extend the OLE period
beyond 50 weeks based on emerging safety data.
SAMPLE SIZE: The study is planned to enroll approximately
50 subjects. The sample size
will enable a statistical power of 80%, at 1-sided significance level of
0.025,
to test against the null hypothesis of endoscopic improvement rate of12%,
assuming the endoscopic improvement rate for A219 is 27%.
SUBJECT TYPE: Male or female subjects > 18 years of age
with moderately to severely
active CD.
FORMULATIONS: A219 will be supplied in 10 mL vials each
containing 500 mg A219(60
mg/mL solution) for IV administration after reconstitution.
DOSAGE: Induction Period: all subjects will receive
A219 1000 mg on Week
0/Day 1, followed by 500 mg IV on Weeks 2,6, and 10.
Non-responders at Week 12 should be discontinued from the study.
Responders at the end of Week 12 have the option to enter the OLE, where
subjects with deep remission will undergo therapy withdrawal and subjects
without deep remission will be randomized to receive one of the following
regimens until disease progression, withdraw from the study, study
termination, or Week 50:
= A219 250 mg IV on Week 14 then Q4W
= A219 100 mg IV on Week 14 then Q4W
Subjects who do not respond by the end of Week 12 should be discontinued
from the study.
All subjects who develop disease relapse (defined as CDAI > 220 and either
hsCRP > 5 mg/L and/or fecal ealprotectin > 250 g/g), after therapy
withdrawal will receive another course of induction therapy (1000 mg IV
followed by 500 mg IV 2, 6, and 10 weeks after the first infusion) followed
by maintenance therapy of 250 mg IV Q4W for a total of 50 weeks.
ROUTE OF The study drug will be reconstituted in 250
mL of 0.9% normal saline (NS)
ADMINISTRATION: and will be administered IV over 30 minutes.
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STUDY ENDPOINTS: Primary endpoints:
= Safety and tolerability: the proportion of subjects reporting adverse
events (AEs), serious adverse events (SAEs), AEs leading to
discontinuation, and markedly abnormal laboratory values
= The proportion of subjects with endoscopic improvement, as defined by
decrease in SES-CD > 50% from Baseline at Week 12
Secondary endpoints:
= The proportion of subjects in clinical remission (CDAI < 150) at
Week 12
= The proportion of subjects with endoscopic and clinical improvement,
as defined by decrease in SES-CD > 50% AND reduction in CDAI
> 100 points from Baseline at Week 12
= The proportion of subjects with both biomarker and clinical
improvement (decrease in hsCRP OR fecal calprotectin > 50% from
Baseline, among subjects with at least one elevated biomarker at
Baseline, AND reduction in CDAI > 100 points from Baseline) at Week
12
= The proportion of subjects with normalization of hsCRP (as defined by
hsCRP < ULN), among subjects with elevated concentrations at Baseline,
at Week 12
= The proportion of subjects with normalization of fecal calprotectin
(as defined by fecal calprotectin < ULN), among subjects with elevated
concentrations at Baseline, at Week 12
= The proportion of subjects in clinical response, as defined by reduction
in CDAI > 100 points from Baseline at Week 12
= The proportion of subjects with PRO-2 remission (defined as average
daily abdominal pain score < 1 point and average daily stool frequency
<3 points with abdominal pain and stool frequency no worse than
Baseline) at Week 12
= Change in SES-CD score at Week 12 from Baseline
= Descriptive summaries of PK and immunogenicity of A219
= Proportion of subjects developing anti-drug antibody (ADA) and
neutralizing antibody (Nab)
Exploratory endpoints:
= Change in CDAI and components from Baseline over time
= Change in PD markers including TL1A concentrations, EHI, fecal
calprotectin, and hsCRP over time
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= Change in SES-CD from Baseline at Week 50
= Change in PDAI from Baseline over time
= Proportion of subjects with improvement or remission of
enterocutaneous and/or perianal fistula at Week 12 and Week 50
= Change in GHAS and RHI from Baseline to Week 12 and Week 50
= The proportion of subjects with GHAS histologic score <4 at Week 12
and Week 50
= The proportion of subjects with Robarts histologic score < 5 at Week
12 and Week 50
= The proportion of subjects with GHAS histologic remission, defined as
no neutrophils in the epithelium or subscore of 0, at Week 12 and Week 50
= The proportion of subjects with Robarts histologic remission (< 3) at
Week 12 and Week 50
= Time to relapse among subjects with deep remission at Week 12
= Proportion of subjects who relapse, among subjects who achieved deep
remission at Week 12
= Change in PRO-2 overtime
= The proportion of subjects with extraintestinal manifestation through
Week 50
INCLUSION Subjects are required to meet the following
criteria in order to be included in
CRITERIA: the study:
1. Male or female? 18 years of age.
2. Subjects must have had a documented diagnosis of CD (endoscopy +
histology) to be eligible for study participation. For subjects with no
documented confirmation of CD diagnosis or if previous diagnosis isnot
deemed conclusive, CD diagnosis must be confirmed at time of screening
colonoscopy.
3. Moderately to severely active CD as defined by CDA1 of? 220 and
<450.
4. SE S-CD score (per central reading) > 6 if ileocolonic or colonic
disease; or? 4 if isolated ileal disease only.
5. Subjects must satisfy at least one of the following criteria:
a) In the past, had an inadequate
response to one or more of the
following treatments:
= Oral prednisone > 40 mg/day (or equivalent) or budesonide
> 9 mg/day or equivalent or beclomethasone > 5 mg/day for at least 2
weeks
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= Corticosteroid dependence as defined by failed to successfully
taper to < 10 mg/day of prednisone or equivalent (i.e., had a flare of
disease) within 3 months of starting therapy, or if relapse occurs within 3
months of stopping corticosteroids
= Immunosuppressants (azathioprine > 2 mg/kg/day or
6-mercaptopurine > 1.0 mg/kg/day, [or documentation of atherapeutic
concentration of 6-thioguanine nucleotide] or methotrexate > 15
mg/week) for at least 8 weeks
= An approved anti-TNF agent at an approved labeled dose for at
least 8 weeks
= An approved anti-integrin (e.g., vedolizumab) at an approved
labeled dose for at least 8 weeks
= An approved anti-IL-12/23 (e.g., ustekinumab) at an approved
labeled dose for at least 8 weeks
OR
b) Had been intolerant to one or more_of
the above mentioned
treatments (e.g., unable to achieve doses or treatment durations because of
dose-limiting side effects [e.g., leukopenia, psychosis, uncontrolled
diabetes, elevated liver enzymes])
OR
c) Currently receiving one or more of
the following treatments:
= Oral Prednisone 20 mg/day (or equivalent) or budesonide
> 3 mg/day for at least 4 weeks
= Immunosuppressants [azathioprine 2 mg/kg/day or
6-mercaptopurine 1.0 mg/kg/day, (or documentation of a therapeutic
concentration of 6-thioguaninc nucleotide)] for atleast 8 weeks
Notes on subjects who have had prior approved biologic therapy(ies) (e.g.,
anti-TNF, anti-integrin, and/or anti-IL-12/23):
= The study will include a maximum of 70% subjects who have had
prior approved biologic therapy(ies) experience. Upon reaching the
maximum number of allowed biologic experienced subjects (70%), subjects
who have had prior biologic experience will no longer be allowed to enter
the study.
= Subjects cannot have had failed (no response, insufficient response,
loss of response, and/or intolerance) >4 approved biologic therapies,
whether of same or different mechanism of action
= Subjects previously on clinical trials only (i.e., did not receive
commercial available therapy post-approval) are not considered to have
received the approved therapy for purpose of this inclusion criteria
6. For subjects who are women of childbearing potential (WOCBP)
involved in any sexual intercourse that could lead to pregnancy, the
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subject has used two highly effective methods of contraception for at least
4 weeks prior to Day 1 and agrees to continue to use two highly effective
methods of contraception until at least 12 weeks after the last dose of study
drug.
7. Male subjects must use, with their female
partner of childbearing
potential, two highly effective methods of contraception and refrain from
sperm donation from screening to 12 weeks after the last dose of study
drug.
8. Subjects must meet drug stabilization
requirements, as applicable:
a) Oral corticosteroid treatment must be equivalent of < 20 mg
prednisone or <9 mg budesonide or beclomethasone < 5 mg daily at a
stable dose for at least 2 weeks prior to Day 1
b) Oral aminosalicylates should be at a stable dose for at least 2
weeks prior to Day 1
c) Azathioprine, 6-mercaptopurine, and methotrexate should be at a
stable dose for at least 4 weeks prior to Day 1
9. Able to provide written informed consent
and understand and comply
with the requirements of the study.
EXCLUSION Subjects with the following characteristics
will be excluded from the study:
CRITERIA: Sex and Reproductive Status
1. WOCBP and men with female partners of childbearing potential who
are unwilling or unable to use two highly effective methods of
contraception to avoid pregnancy for the entire study period and for upto
12 weeks after the last dose of study drug.
2. Women who are pregnant or breastfeeding.
3. Women with a positive pregnancy test on enrollment or prior to Day 1.
Target Disease Exceptions
4. Diagnosis of ulcerative colitis or indeterminate colitis.
5. CD isolated to the stomach, duodenum, jejunum, or perianal region,
without colonic and/or ileal involvement.
6. Suspected or diagnosed intra-abdominal or perianal abscess at
Screening.
7. Known symptomatic stricture or stenosis not passable in endoscopy
(including pediatric colonoscope).
8. Current stoma or need for colostomy or ileostomy.
9. Previous small bowel resection with combined resected length of
> 100 cm or previous colonic resection of > 2 segments.
10. Currently receiving total parenteral nutrition.
11. Surgical bowel resection within 3 months before screening.
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12. Concomitant primary sclerosing
cholangitis (PS C).
Medical History and Concurrent Diseases
13. Past or current evidence of definite low-
grade or high-grade colonic
dysplasia that has not been completely removed.
14. Subjects who are scheduled or anticipate the need for surgery, aside
from dennatologic procedures.
15. Subjects who have a history of clinically
significant drug or alcohol
abuse.
16. Concomitant illness that in the opinion
of the Investigator, is likely
to require systemic glucocorticosteroid therapy during the study (e.g.,
moderate to severe asthma).
17. Current symptoms of severe, progressive,
or uncontrolled renal,
hepatic, hematological, pulmonary, cardiac, neurological,
ophthalmologic, or cerebral disease. Concomitant medical conditionsthat
in the opinion of the Investigator might place the subject at unacceptable
risk for participation in this study.
18. Subjects with a history of cancer within
the last 5 years (other than
non-melanoma skin cell cancers cured by local resection). Existing non-
melanoma skin cell cancers must be removed prior to enrollment. Subjects
with carcinoma in situ or localized cervical cancer, treated with definitive
surgical intervention, are allowed.
19. Subjects at risk for tuberculosis (TB). Specifically, subjects with:
a) A history of active TB
b) Current clinical, radiographic_ or laboratory evidence of active TB
e) Latent TB which was not successfully
treated. Subjects with a
positive TB screening test indicative of latent TB will not be eligible for
the
study unless active TB infection has been ruled out, and an appropriate
course of intervention for latent TB has been initiated at least 2 weeks prior
to Day 1, and no evidence of active TB on chest x-ray during screening.
20. Subjects with any serious bacterial infection within the last 3 months,
unless treated and resolved with antibiotics, or any chronic bacterial
infection (such as chronic pyelonephritis, osteomyelitis, and
bronchiectasis).
21. Female subjects who have had a breast cancer screening that is
suspicious for malignancy, and in whom the possibility of malignancy
cannot be reasonably excluded following additional clinical, laboratory,or
other diagnostic evaluations.
22. Subjects with any active infections
(excluding fungal infections of nail
beds) including, but not limited to, those that require IV antimicrobial
treatment 4 weeks or oral antimicrobial treatment 2 weeks prior to
randomization. Subjects with evidence of Human Immunodeficiency
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Virus (HIV), Hepatitis B, or Hepatitis C infection detected during screening
are also excluded, but subjects with successfully treated Hepatitis C with no
recurrence for > 1 year are allowed. Subjects with active documented or
suspected COVID-19 infection within 4 weeks ofrandomization or
asymptomatic SARS-CoV-2 PCR test within 2 weeks of randomization are
excluded.
23. Subjects with herpes zoster reactivation or cytomegalovirus (CMV)
that resolved less than 2 months prior to signing informed consent.
24. Subjects who have received any live
vaccines within 3 months of the
anticipated first dose of study medication or who will have need of alive
vaccine at any time during the study.
Physical and Laboratory Test Findings
25. Positive stool Polymerase Chain Reaction (PCR) or culture for enteric
pathogens.
26. Stool positive for Clostridium difficile (C. difficile) toxin. Subjects
who
are positive can be retested after the completion of a full course of
treatment
for C. difficile infection.
27. Any of the following lab values:
a) Hemoglobin (Hgb) < 8.0 g/dL (80 g/L)
b) Whitc blood cell (WBC) < 2,500/mm3 (2.5 x 109/L)
c) Neutrophils < 1,000/mm3 (1 x 109/L)
d) Platelets < 100,000/mm3 (100 x 109/L)
d) Serum creatinine > 2 times ULN
e) Serum alanine aminotransferase (ALT) or aspartate
aminotransferase (AST) > 2 times ULN
Any other laboratory test results that, in the opinion of the
Investigator, might place the subject at unacceptable risk for
participation in this study.
Prohibited Therapies and/or Medications
28. Failed (no response, insufficient
response, loss of response, and/or
intolerance) > 4 approved biologic therapies (anti-TNF, anti-integrin,anti-
IL12/23), whether of same or different mechanism of action.
29. Any marketed biologic within 8 weeks for anti-TNF agents and 12
weeks for anti -integrin agents (e.g., vedolizumab) and ustekinumabprior
to Day 1 or if drug level per therapeutic dose monitoring is greater than
lower limit of detection.
30. Any biologic immunomodulators used for CD or other conditions
within 8 weeks or 5 half-lives, whichever is longer, prior to Day 1 or ifdrug
level per therapeutic dose monitoring is greater than lower limit ofdetection.
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31. Rituximab within 1 year prior to Day 1.
32. Parenteral corticosteroids within 4 weeks or rectal administration of
corticosteroids within 2 weeks prior to Day 1.
33. Rectal administration of 5-A SA within 2 weeks prior to Day 1.
34. Tacrolimus, cyclosporine, mycophenolate mofetil (CellCept ,
immunoadsorption columns (such as Prosorba columns), D Penicillamine,
Leflunomide, Thalidomide, chronic use of non-steroidalanti-inflammatoty
agents (NSAIDs), and aspirin > 81 mg/day within 2 weeks prior to Day 1.
35. Other investigational chemical agent within 30 days or other
investigational biologic agent within 8 weeks or 5 half-lives (whicheveris
longer) of entry into the IP.
36. Prior exposure to A219.
Other Exclusion Criteria
37. Prisoners or subjects who are compulsorily detained (involuntarily
incarcerated) for treatment of either a psychiatric or physical
(e.g., infectious disease) illness.
38. Legal or mental incapacitation, or inability to understand and comply
with the requirements of the study.
Statistical Methods: Statistical methods will be detailed in the
Statistical Analysis Plan (SAP).
The SAP will provide details about methods of analysis and the specific
planned analyses, and will be prepared and approved by Prometheus
Biosciences and its designees before study database lock.
The analysis populations are defined as follows:
= Full analysis set (FAS): all subjectstreated with Baseline SES-CD score
= Safety analysis set: all subjects treated
The following analyses will be performed:
Efficacy:
The primary efficacy endpoint, endoscopic improvement at Week 12, will
be used to assess the efficacy of A219. The proportion of subjects in FAS
with endoscopic improvement will be tested against the null hypothesis of
endoscopic improvement rate of 12%, at a 1-sided significance level of
0.025. If significant, the 1st secondary endpoint of proportion of subjects
achieving clinical remission will be tested against the null hypothesis of
clinical remission rate of 16%, at a 1-sided significance level of 0.025.
The point estimates for the primary and secondary endpoints will be
calculated along with 90% confidence interval for FAS and by companion
diagnostic (CDx) status (CDx+ or CDx-).
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Adverse Events:
AEs will be coded using the most current version of Medical Dictionary for
Regulatory Activities (MedDRA@).
A by-subject AE data listing, including verbatim term, preferred term (PT),
system organ class (SOC), treatment, severity, seriousness criteria,
relationship to drug, and action taken, will be provided.
The number of subjects experiencing treatment-emergent adverse events
('TEAEs) and number of TEAEs will be summarized by treatment using
frequency counts in safety analysis set.
Medical History, chest x-ray, electrocardiogram (ECG), and physical
examination will be listed by subject.
Changes in ECGs and physical examinations will be described in the text of
the final report.
Concomitant Medications:
Concomitant medications will be coded using the most current World
Health Organization (WHO) drug dictionary and listed by treatment.
Pharmacokinetics:
Summary statistics of A219 concentrations and ADA by visit.
Example 24: Formulation Verification Study.
1005401 Exemplary formulations provided herein were placed on long-term
stability
studies (up to six months). This Example summarizes the results of these
storage stability
studies.
1005411 Materials used in this study include A219 at various concentrations as
indicated.
1005421 METHODS AND PROCEDURES
1005431 UV Analysis. The sample absorbance and sample concentration were
measured
by standard UV absorbance instrument, using an extinction coefficient of
1.41mL. mg-1 cm-
1, and correcting background scattering.
1005441 pH Analysis. Before the start of analysis, the pH probe was calibrated
with three
pH standards ordered from fisher. The pH of the formulation will be measured
by inserting
the pH probe into the sample and waiting until the measured value has
stabilized, which can
take up to 1 to 2 minutes.
1005451 Osmotic Analysis. The osmotic analysis was performed using an Advanced
Instruments Osmo 1. At the start of analysis, a reference standard at 290 mOsm
is analyzed to
ensure the instrument is working properly. After the reference standard has
passed the
samples are then analyzed. 20uL of sample material is removed and analyzed by
the Osmo 1.
1005461 Viscosity. The viscosities of the samples were measured using m-Vroc
from
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Rheosense (San Ramon, CA, USA). The dynamitic viscosity of sample was
calculated by
flowing the samples past three difference pressure sensors. The linear
regression of the
pressure drop from the three sensors was then used to calculate dynamitic
viscosity of the
samples. The instrument was calibrated and the dynamitic viscosity of the
samples were
measured according to manufacturer's instructions and industry standards. The
analysis
parameters for sample concentrations ranging from 60 to ¨230 mg/mL are listed
in Table 30:
Table 30. Viscosity parameters for assessing protein samples
A219
Measurement Waiting
concentration Shear Rate, 1/s
Time, s Time, s
(mg/mL)
60 1000 1.9 3
150 1000 1.9 3
175 1000 1.9 3
200 1000 1.9 3
[00547] Size Exclusion Chromatography (SEC). The SEC method was used to
measure
the stability of the protein samples.
[00548] Cation Exchange Chromatography (CEX). The CEX was also used to measure
the stability of the protein samples.
[00549] Flow Imaging (FlowCam). Measurements of particle counts in the samples
were
made using a Model VS-1 FlowCAM flow imaging system (SN 551) with Sony SX90
camera and C70 pump with a 1 mL syringe (Fluid Imaging Technologies). The
system
qualification consisted of obtaining acceptable bead counts using an NIST
certified count
standard (PharmTrol, Thermo, catalogue no. CS3800-15 or similar) along with
acceptable
procedural blanks (water). The acceptance criteria used for the count standard
was 3800
15% and no more than 1 count/mL greater than or equal to 10 lam for the water
blank.
Samples were visually assessed during the sample run and if needed adjustments
were made
to optimize the results of each run. An x-y flow plot was recorded for each
sample run.
[00550] Study Design. The verification study examined formulations with A219
concentrations ranging from 60 to 200 mg/mL as shown in Table 31 (formulations
1-9 as
Form. 1-9 in the table, or F01-F08 in this Example). The storage stability
study plan is shown
in Table 32.
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Table 31. Formulations tested in this study
A219
Acetate Sucrose Lys-HCL NaC1 PS 20
Form. Concentration pH
(mM) (mM) (mM) (mM) (%)
(mg/mL)
1 60 pH 6.5, 20 mM PO4, 5% Sucrose, 20 mM
0.01
Glycine
2 60 5.3 20 240 25 0 0.02
3 150 5.3 20 240 25 0 0.02
4 175 5.3 20 240 25 0 0.02
200 5.3 20 240 25 0 0.02
6 150 5.3 20 220 0 40 0.02
7 175 5.3 20 220 0 40 0.02
8 200 5.3 20 220 0 40 0.02
Table 32. Study Design
Temp. C TO 1 Month (1M) 2 Month (2M) 3 Month (3M) 6 Month (6M)
5 X X X X X
25 X X X X
Notes for Table 32: Initial Time point (TO): pH, osmolality, viscosity; at the
end of each
storage condition: visual inspection SEC and CEX and others as described in
this Example.
Each time point (1M, 2M, 3M, 6M): Visual Inspection, SEC and CEX and others as
described
in this Example
1005511 RESULTS
[00552] The control (TO) samples listed in Table 31 were characterized by
visual
inspection, osmolality (osmo), pH, protein concentration, viscosity, SEC, CEX
and Flow
Cam. The remaining times were analyzed by SEC and CEX except that the last
time point of
each temperature in Table 32 was characterized by the same measurements in TO.
[00553] Visual Characterization
1005541 The bulk material used for these studies had a slight yellow
tint, but was otherwise
clear with no visual particles observed. The formulations at TO were visually
inspected and
were clear with no visible particles observed. At 60 mg/mL, formulations 1 and
2, had slight
yellow tint, the tint became more intense as the concentration increased from
60 mg/mL to
200 mg/mL. A summary of the visual observations can be found in Table 33.
Throughout the
study, no visible particles were observed and the samples remained clear under
all conditions.
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Table 33. Visual characterization of the stability samples
Visual Visual Visual Visual
Visual
Form' (1M5) cm) Visual (1M25) (2M25) (3M5)
Visual (3M25)
(6M5)
1 C,NP,NC C,NP,NC C,NP,NC C,NP,NC C,NP,NC C,NP,NC C,NP,NC
2 C,NP,NC C,NP,NC C,NP,NC C,NP,NC C,NP,NC C,NP,NC C.NP,NC
3 C,NP,NC C,NP,NC C,NP,NC C,NP,NC C,NP,NC C,NP,NC C,NP,NC
4 C,NP,NC C,NP,NC C,NP,NC C,NP,NC C,NP,NC C,NP,NC C,NP,NC
C,NP,NC C,NP,NC C,NP,NC C,NP,NC C,NP,NC C,NP,NC C,NP,NC
6 C,NP,NC C,NP,NC C,NP,NC C,NP,NC C,NP,NC C,NP,NC C,NP,NC
7 C,NP,NC C,NP,NC C,NP,NC C,NP,NC C,NP,NC C,NP,NC C.NP,NC
8 C,NP,NC C,NP,NC C,NP,NC C,NP,NC C,NP,NC C,NP,NC C,NP,NC
C¨Clcar, NP¨No Particles, NC¨No Color
[00555] Osmo/a/i0;
[00556] The osmotic pressure was measured for the stability samples at TO, 3
and 6
months (Table 34). In addition, the theoretical osmolality was calculated for
all formulations,
except for formulation 1. The osmotic pressure for the samples ranged from 223
to 487
mOsmol/kgH20 for the highest protein concentrations (Table 34). The
differences in the
osmotic pressure between theoretical and measured become larger as the protein
concentration increased from 60 to 200 mg/ml, reflecting the increasing
contribution from the
protein. Overtime, the osmolality values do increases slightly for some
formulations (FIG.
20), but the differences are relatively minor.
Table 34. Osmotic pressure was measured at TO, 3 and 6 months
Form. Theoretical Osmolality mOsmoTO
mOsmo3M5 C mOsmo3M25 C mOsmo6M5 C
1 n.a 223 232 227
235
2 369 385 374 371
370
3 412 436 414 425
434
4 426 463 431 450
431
5 441 466 494 472
480
6 415 414 412 416
417
7 429 438 436 429
445
8 445 487 460 472
477
[00557] Protein Concentration
[00558] The A219 protein concentration was measured to evaluate the stability
of samples
at TO, 3 and 6 months as shown in Table 35. Most of the values appear to be
unchanged
within the estimated error of the protein concentration method, indicating
that the A219 is
stable in these formulations (Table 35 and FIG. 21). The plot of the measured
A219 protein
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concentrations in each samples after 0, 3 and 6 months shows that the
concentrations are
fairly constant and likely do not reflect any substantive changes in protein
content (FIG. 21).
Moreover, the protein concentrations were all within 5% of the target
concentration for the
formulation.
Table 35. Protein concentration was measured at TO, 3 and 6 months
M5 C 3M25 C
Form. (mg/mL) TO (mg/mL) 3 6M5 C (mg/mL)
(mg/mL)
1 60 60.05 59.73 59.53 56.54
2 60 61.88 63.01 62.13 61.87
3 150 150.32 150.13 149.89 147.56
4 175 174.18 174.91 175.03 173.18
200 204.54 204.34 204.26 198.39
6 150 149.45 150.24 149.22 148.45
7 175 173.16 173.95 173.69 173.51
8 200 203.17 201.42 203.39 198.66
[00559] pH Measurements
[00560] The pH values were measured to evaluate the stability of samples at
the 0, 3 and 6
month time points (Table 36). The measured pH values were all within less than
0.1 of the
target pH for the formulation. The constancy of the pH values is shown in FIG.
22.
Table 36. pH values measured at TO, 3 and 6 months.
Form. pH pH TO pH 3M5 C pH 6M5 C pH 3M25 C
1 6.5 6.50 6.48 6.47 6.46
2 5.3 5.34 5.29 5.30 5.31
3 5.3 5.35 5.32 5.32 5.33
4 5.3 5.35 5.33 5.33 5.34
5 5.3 5.36 5.34 5.34 5.35
6 5.3 5.32 5.31 5.32 5.32
7 5.3 5.33 5.31 5.32 5.33
8 5.3 5.33 5.33 5.33 5.34
1005611 Viscosity Measurements
[00562] The viscosities were measured to evaluate the stability of A219
samples of various
formulations at TO, and after 3 and 6 months as shown in Table 37. FIGs. 23A
and 23B
show the graphical representation of the viscosity data vs protein
concentration at TO,
consistent with an exponential response and with the viscosity of mAbs
behaving as function
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of concentration.
[00563] For formulations 6-8, the viscosity data ranges from about 5.3 to 13.4
mPa*s as
protein increased from -150 to -200 mg/mL. By comparison, formulations 3-5
have a
somewhat higher viscosity, ranging from about 6.3 to 16.0 mPa*S over the same
protein
concentration range. Upon storage, some of the formulations do exhibit
slightly higher
viscosity values, possibly due to slightly increased levels of aggregates (see
below).
Table 37. Viscosity was measured at TO, 3 and 6 months.
Lys-
Acetate Sucrose PS 20 Viscosity
Viscosity Viscosity
Form. (mg/mL) pH NaCl(mM) HCL
(mM) (mM) (%) TO 3M25C 6M5C
(mM)
1 60 20 mM Po4, 5% Sucrose, 20mM Glycine' 0.01 1.51
1.45 1.78
0.01% PS 20
2 60 5.3 20 240 25 0 0.02 1.48 1.72
1.96
3 150 5.3 20 240 25 0 0.02 6.26 6.43
6.68
4 175 5.3 20 240 25 0 0.02 8.93 9.17
10.75
200 5.3 20 240 25 0 0.02 16.01 19.67 20.34
6 150 5.3 20 220 0 40 0.02 5.31 6.01
5.91
7 175 5.3 20 220 0 40 0.02 7.23 9.14
10.41
8 200 5.3 20 220 0 40 0.02 13.41
19.48 17.78
[00564] Stability measurements by Size Exclusion Chromatography (SEC)
[00565] The stability of the A219 samples was characterized by size exclusion
chromatography (SEC). At TO, the monomer content was >98% for these samples
(Table
38). After two months at 25 C, the monomer content only slightly decreases,
with all
formulations retaining > 97% monomer. Even after three months at 25 C, the
monomer
contents remain near 97%. When stored at 5 C, the loss of monomer (primarily
due to
formation of higher molecular weight (HMW) species) averages only about 0.2-
0.4% (Table
39).
Table 38. TO, 1 and 2 month SEC results for A219 samples
1M25 C (Rel. Area 2M25
C (Rel. Area
TO (Rel. Area %) 1M5 C (Rel. Area %)
A)
0A)
Form.
Main Main Main
Main
HMW LMW HMW LMW HMW LMW HMW
LMW
Peak Peak Peak
Peak
1 1.46 98.46 0.08 1.44 98.48 0.08 1.85 98.02 0.13 2.04 97.77
0.19
2 1.25 98.67 0.08 1.26 98.67 0.07 1.4 98.44 0.15 1.52 98.25
0.23
3 1.54 98.39 0.07 1.59 98.34 0.08 1.91 97.95 0.14 2.12 97.66
0.21
4 1.67 98.25 0.07 1.67 98.25 0.07 2.02 97.84 0.14 2.26 97.53 0.21
5 1.74 98.19 0.06 1.75 98.19 0.07 2.20 97.66 0.14 2.50 97.29
0.21
6 1.57 98.37 0.06 1.56 98.38 0.06 2.01 97.85 0.14 2.28 97.50 0.22
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7 1 1.65 1 98.291 0.06 1 1.65 1 98.21 0.06 1 2.14 97.73
0.14 2.44 1 97.35 0.21 1
8
1.76 98.17 0.06 1.77 98.17 0.06 2.34 97.52 0.14 2.64 97.15 0.21
1005661 The small loss of monomer is shown in the graph in FIG. 24A. It
appears that
formation of aggregates (HMW species) is increased som ewhat at higher
concentrations for
high concentration formulations 3-8. The overall monomer loss per month for
samples stored
at 5 C is only about 0.04 to 0.06% FIG. 24B. The monomer levels for the 25 C
samples are
provided in FIG. 24C. The average loss per month for these samples is about
0.3 to 0.4% per
month as shown in FIG. 24D. Based on these data, there would be less than 1%
loss of
monomer at 5 C over two years and less than 5% loss of monomer when stored at
25 C.
Table 39. Summary of 3 and 6 month SEC results for A219 samples
3M5 C (Rel. Area %) 3M25 C (Rel. Area %) 6M5 C
(Rel. Area %)
Form.
HMW Main Peak LMW HMW Main Peak LMW HMW Main Peak LMW
1 1.54 98.39 0.07 2.20 97.54 0.27
1.72 98.19 0.09
2 1.29 98.63 0.07 1.65 98.03 0.31
1.40 98.51 0.09
3 1.62 98.31 0.07 2.32 97.39 0.29
1.81 98.10 0.09
4 1.69 98.24 0.07 2.53 97.18 0.29
1.89 98.02 0.09
1.84 98.09 0.07 2.76 96.95 0.29 2.01 97.90
0.09
6 1.67 98.27 0.06 2.76 96.95 0.29
1.89 98.01 0.09
7 1.74 98.19 0.07 2.52 97.19 0.29
1.98 97.93 0.09
8 1.88 98.06 0.07 2.68 97.03 0.29
2.09 97.82 0.09
1005671 Stability measured by Cation Exchange Chromatography (CEX)
1005681 The stability of the A219 samples were characterized by cation
exchange
chromatography (CEX). The CEX data for the 0, 1, and 2 month time points are
summarized
in Table 40. The relative area of the main peak started near 65%. Overtime,
this decreased,
primarily due to increases in the acidic species, indicating some hydrolytic
change, such as
deamidation, was occurring. Formulation 1 (F01) shows the greatest changes.
Table 40. A219 samples characterized by cation exchange chromatography at TO,
1
and 2 month
TO (Rel.Area %) 1M5 C (Rel.Area %) 1M25 C (Rel.Area %)
2M25 C (Rel.Area %)
Form. = Main Main Main
Main
Peak
Acid Basic Acid Peak Basic Acid Peak Basic Acid Peak Basic
1
32.21 65.33 2.46 33.47 64.16 2.38 40.44 56.81 2.75 46.26 51.08 2.66
2 32.15 65.18 2.67 32.67 64.67 2.66 36.63 60.01 3.35 40.42 56.13 3.45
3
32.23 65.17 2.60 32.68 64.52 2.80 36.43 59.89 3.67 40.20 56.07 3.73
4 32.14 65.08 2.78 32.69 64.46 2.84 36.37 59.87 3.76 40.01 56.15 3.84
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32.24 65.01 2.75 32.62 64.46 2.92 36.38 59.74 3.88 39.97 56.10 3.93
6 32.28 65.09 2.63 32.72 64.36 2.92 36.42 59.77 3.80 40.00 56.15 3.85
7 32.26 65.04 2.69 32.58 64.60 2.83 36.23 59.95 3.82 39.95 56.22 3.83
8
32.44 64.82 2.74 32.74 64.33 2.94 36.26 59.80 3.94 39.78 56.21 4.02
Table 41. A219 samples characterized by cation exchange chromatography at TO 3
and 6 month
3M5 C (Rel . Area %) 3M25 C (Rel . Area %) 6M5 C
(Rel.Area %)
Form. Main Main
Main
Pe Peak Pe
Acid Basic Acid Basic Acid
Basic
ak
ak
1 34.39 63.23 2.38 51.34 45.88 2.78 35.56
61.84 2.61
2 34.18 63.2 2.62 44.3 51.79 3.9 33.33
63.89 2.78
3 32.84 64.28 2.88 43.84 51.89 4.27 33.23
63.76 3.01
4 32.77 64.34 2.89 43.87 51.66 4.47 33.2
63.67 3.13
5 32.72 64.32 2.96 43.68 51.67 4.66 33.17
63.66 3.17
6 32.83 64.26 2.91 43.69 51.83 4.48 33.22
63.73 3.05
7 32.74 64.42 2.84 6.97 50.98 0.98 33.17
63.73 3.1
8 32.72 64.26 3.02 43.49 51.81 4.7 33.18
63.66 3.16
1005691 After three months at 25 C, the main peak averaged near 51%, while
FOI
continues to show greater decrease with only about 46% main peak relative area
(Table 41).
By comparison, samples stored at 5 C exhibit very little decrease in CEX
measurements.
Even after six months, the relative area of the CEX main peak remains near 63%
for
formulations 2-8. Changes in the relative area of the CEX main peak are shown
in FIG. 25A.
Meanwhile, all of the high concentration (A219 at or above 150 mg/ml)
formulations showed
comparable stability by CEX. The rate of loss at 5 C is provided in FIG. 25B
and
formulations 2-8 have very good stability as determined by CEX.
1005701 The CEX stability profiles at 25 C are seen in FIG. 25C. The decrease
in the
main peak, presumably by hydrolytic changes, are more pronounced at 25 C than
at 5 C.
The rates of decrease per month at 25 C are about 20 times greater than at 5
C (FIG. 25D).
1905711 Stability Measurements by FlowCAM Flow Imaging Analysis
1005721 The stabilities of these samples were characterized by FlowCAM, which
counts
the number of subvisible particles (SVPs) in various size bins. The levels of
SVPs are all
reported in particle per mL. At TO, the particle counts are higher for F01
than the other
formulations (Table 42). However, at one month/5 C, the particle levels for
F01 were not
comparable to the other preparations. Results for the FlowCAM analysis for
samples held at
25 C after one and two months are shown in Table 43. Levels in all of the
formulations
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remain relatively low after two months at 25 C (Table 43) and three months as
well (Table
44). The SVP levels for samples held at 5 C for three months appear to be
even slightly
lower than for the corresponding 25 C samples (Table 44). Finally, samples
held for six
months at 5 C were analyzed, and the levels of SVPs remained low as shown
(Table 45).
Table 42. FlowCAM Analysis for TO and 1 Month stability samples
Time Point: 0
Time Point: 1 Month 5 C
Form Gi ' E 2 G 'I 'It' GTE Gi 'It' G 'I E G1 E GT 1i: GI E G TE GTE
urn 3 urn 5 urn 10 urn 25 urn 2 urn 3 urn 5
urn 10 urn 25 urn
Fl 141512 63887 25534 3612 439 3771 2096 1450 474
13
F2 7163 2994 1226 250 79 3244 1331 447 131 26
F3 2901 1647 698 184 26 1332 594 343 92 13
F4 2413 1226 553 184 26 2466 1253 633 132 39
F5 3640 1872 1081 527 92 949 343 277 145 0
F6 2848 1371 738 250 39 4813 2690 1358 448 105
F7 13676 8800 4876 1105 0 18122 8000 3103 463
40
F8 4432 1979 1188 317 53 1543 949 395 79 0
Table 43. FlowCAM Analysis for 1 and 2 Month stability samples
Time Point: 1 Month 25 C
Time Point: 2 Month 25 C
Form GTE GTE GTE GTE 10 GTE GTE GTE GTE GTE GTE
2 urn 3 urn 5 urn urn 25 urn 2 urn 3 urn 5 urn 10 urn
25 urn
Fl 4023 1900 779 251 13 3864 2308 1464 567 158
F2 23330 11129 4660 897 26 1094 554 303 66
13
F3 2453 1212 513 65 13 1305 751 355 52 0
F4 8854 4024 1952 435 53 435 317 198 79 13
F5 2526 1477 658 215 40 514 304 172 93 0
F6 4749 2071 1003 238 40 382 171 79 26
0
F7 1477 686 396 145 13 686 197 52 39 13
F8 3798 2163 1174 356 79 356 237 171 105 26
Table 44. FlowCAM Analysis for 3 Month stability samples
Time Point: 3 Month 5 C
Time Point: 3 Month 25 C
Form GTE GTE GTE GTE 10 GTE GTE GTE GTE GTE GTE
2 um 3 um 5 um um 25 urn 2 um 3 um 5 um 10 um 25 um
Fl 1807 791 237 26 0 4340 1846 778 184 65
F2 1081 448 145 66 13 3509 1292 369 66 26
F3 3877 1464 52 53 0 1490 619 237 52
13
F4 1002 528 251 119 0 1925 725 198 53 13
F5 1029 277 92 13 13 857 370 185 40
0
F6 2796 1239 487 144 26 2136 937 172 40
0
F7 1609 830 395 26 0 5144 2282 884 132
0
F8 2347 962 303 26 0 2268 1029 502 40 40
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Table 45. FlowCAM Analysis for6 Month stability samples
Time Point: 6 Month 5*C
Form
GTE 2 urn GTE 3 urn GTE 5 um GTE 10 um
GTE 25 urn
Fl 6079 2967 1332 462 92
F2 2110 989 409 145 66
F3 6345 2849 1081 237 79
F4 1055 565 249 91 39
F5 1846 777 250 52 13
F6 5327 2148 1067 263 92
F7 2321 1134 461 224 13
F8 620 263 39 13 13
[00573] PLS Analysis for the 2 Month Samples
[00574] The 25 C 2 month data was used to constructed the PLS models. The
first PLS
model used the Loss MP by SEC after two months at 25 C as the endpoint (FIG.
26A). The
correlation coefficient for the calibration set was 0.975 while the r-value
for the validation set
was 0.776, indicating a model of reasonable quality. The PLS model indicates
the significant
factors influencing the stability of A2 19 include protein concentration,
sucrose, etc.
[00575] This model indicates that monomer loss (e.g., aggregation)
is greater at higher
protein concentrations (FIG. 26B). This effect is much more pronounced than
the pH effect.
The model predicts that lower pH and addition of acetate buffer reduces
monomer loss upon
storage at 25 C (FIG. 26C). Both sucrose and Lys were found to be effective
stabilizers
against aggregation (FIG. 260), while the impact of NaC1 and Gly is small
(FIG. 26E).
1005761 Eight different formulations were placed in longer-term storage at 5
C and 25 C,
and evaluated. Using the acetate buffer system, the pH of each acetate
formulation remains
essentially unchanged upon storage. As for the high concentration A219
samples, the
formulations with sucrose/NaCl clearly reduced viscosity relative to the
sucrose/Lys
formulations, corresponding to about ¨3 cP at 200 mg/ml. The rate of loss of
monomer for
samples in the formulations 2-8 stored at 5 C is quite small, with a total
loss of monomer
after two years predicted to be <1% for all of the high concentration
formulations.
[00577] These compositions appear to have little proclivity to form
particles. There is no
evidence of formation of visible particles and levels of SVPs remains low,
even after six
months of storage. Overall, these high concentration formulations appear to be
quite stable
and they appear to support the use of a 200 mg/ml formulation.
Example 25: Additional Formulation Verification Study.
[00578] An Exemplary A219 formulation (60 mg/mL A219 in 20 mM sodium
phosphate,
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5% (w/v) sucrose, 85 mM glycine, 0.01% (w/y) polysorb ate 20, pH 6.5) was
placed on long-
term stability studies. This Example summarizes the results of the storage
stability studies for
such exemplary formulation.
[00579]
The long-term stability condition tested for anti-TL1A (e.g. A219) was 5+3 C
(Upright). Accelerated stability condition at 25 C/60% RH (Upright) was also
performed. Testing
is performed per the stability protocol presented in Table 46 and Table 47
below. The methods
used for stability testing and acceptance criteria are presented in Table 48
and Table 49. In
addition, a full ICH stability study was also performed for the A219
formulation listed in this
Example (ICH referring to International Council on Harmonization of Technical
Requirements for
Pharmaceuticals for Human Use).
Table 46 A219 formulation Storage Conditions and Sampling Times
Time Point (Months)
Storage Condition
1 3 6 9 12 18 24
36
2-8 C X X X X X, Y X X, Y
X, Y
25 C/60 /oRH X X X X
-20 C X X X X X, Y X X, Y
X, Y
Table 47 Additional A219 formulation Storage Conditions and SamplingTimes
Time Point (Months)
Storage Condition
1 3 6 9 12 18 24
30 36
2-8 C A, B, A, B,
A, B,
ambientrelative humidity, A A A A C, D, A C,
D, A C, D,
Upright orientation A, B,
C, D,
25 C/60%relative E A, B,
humidity, A A
Upright orientation
[00580] Table 48 Methods used for Stability Testing in Table 46
Testing Group Testing Parameter Method
X Appea lance Visual inspection
pH Potentiomenic
Concentration Content UV
Spectrophotometry (280nm)
Non-reduced and reduced CE SDS Capillary
electrophoresis
SEC SEC-UPLC
icIEF Capillary
electrophoresis
Affinity Antigen binding ELI SA
Biological a ctivity (Test initia ted at12 month Cell-ba sed potency a ssay
time point)
Subvisible Particulates USP <787>
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Table 49 Methods used for Stability Testing in Table 47
Testing Group Testing Parameter Method
Appearance Visualinspection
pH Potentiometric
Concentration Content UV Sp
ectrophotometry (280nm)
Extractable volume Gray im etric
A Non-reduced and reduced CE SDS Capillary
electrophoresis
SEC SEC-UPLC
icIEF Capillary
electrophoresis
Affinity Antigen binding ELI SA
Biological activity (Test initiated at6 month Cell-basedpotency assay
time point)
Endotoxin USP <85>
Sterility USP <71>
Subvisible Particulates USP <787>
Extractable volume Gravimetric
[00581] Results from the stability study are shown in Table 50, Table 51, and
Table 52.
Briefly, no significant change in A219 protein quality was observed for up to
12 months of
storage at -20 C or 2-8 C and there have been no out of specification findings
or changes in
the key analysis parameters. The antigen binding affinity and biological
activity are well
preserved at the 6 month, 25 C time point. The biophysical changes seen
indicate that the
formulation is suitable for A219 monoclonal antibody at elevated storage
temperatures for
prolonged periods.
[00582] Results from the ICH stability study are shown in Table 53, and Table
54.
Briefly, no significant change in A219 protein quality was observed for up to
6 months of
storage at 2-8 C and there have been no out of specification findings or
changes in the key
analysis parameters. The antigen binding affinity is well preserved at the 6
month, 25 C time
point. The biophysical changes seen indicate that the formulation is suitable
for A219
monoclonal antibody at elevated storage temperatures for prolonged periods.
- 303 -
CA 03207817 2023- 8-8
to
Table 50 Stability Study: Data for Storage Conditions -20 C
0
Timepoints (in months)
k=.)
kµ.)
Test Initial 1 3 6 9
12 18 24 36
Appearance Conforms Conforms Conforms Conforms Confonns
Conforms
No particulates No particulates No particulates No particulates No
particulates
observed observed observed observed
observed
pH 6.6 6.6 6.6 6.6 6.6
6.6
Concentration 63.6 rn g/mL 63.9 mg/mL 64.6 mg/mL 61.3
mg/mL 62.1 mg/mL 61.8 mg/mL
Non-reduced Intact I gG: 96.9% Intact I gG: Intact I gG: Intact I gG
Intact I gG: Intact I gG
and reduced Total IgG: 96.6% 96.3% 96.6% 95.3% 95.0%
94.9%
CE-SDS HC: 64.5% Total I gG: TotalI gG: TotalI gG:
TotalIgG Tota 1I gG:
LC: 32.2% 96.3% 96.1% 96.6% 96,2%
96.1%
HC: 64.31)/o HC: 64.1% HC: 64.6% HC: 63.7%
HC: 64.0%
LC: 32.0% LC: 31.9% LC: 32.0% LC: 32.4%
LC: 32.1%
SEC 97.4% Monomer 97.1% Monomer 97.2% Monomer 96.2% Monomer
96.1% Monomer 96.5%
2.0% Aggregate 2.2% Aggregate 2.2% Aggregate 3.1% Aggregate
3.2% Aggregate Monomer
2.9%
Aggregate
plicIEF p1=8.8 p1=8.9 p1=8.9 p1=8.9 p1=8.9
p1=8.9
Conforms to Ref Conforms to Ref Conforms to Ref Conforms to Ref Confonns to
Ref Conforms to
Std. Main peak= Std. Main peak= Std. Ma in peak= Std. Ma in
peak= Std. Ma in peak= Ref Std. Main
55.9% 57.1% 55.6% 54.3% 53.0%
peak =52.8%
Acidic =42.4% Acidic =40.9% Acidic =42.2% Acidic =44.1%
Acidic =44.0% Acidic =45.2%
Basic =1.7% Basic =2.0% Basic =2.1% Basics 1.6%
Basic =2.0(1/0 Basic =2.1%
17.J.
Affinity
111% 127% 95% 142% 134%
94%
Biological
NP NP NP NP NP
95%
activity
NP=not performed
n
>
o
L.
r.,
o
-.4
to
174.
r.,
o
r.,
`.'
9'
. Table 51 Stability Study: Data for Storage Conditions 2-8 C
0
kµ.)
o
Timepoints (in months)
k.)
t.).
Test Initial 1 3 6 9
12 18 24 36 i--,
-4
oc
0.
Appeamnce Conforms Conforms Conforms Conforms Confonns
Conforms !A
.0
No particulates No particulates No
particulates No particulates No particuhtes
observed observed observed observed
observed
pH 6.6 6.6 6.6 6.6 6.6
6.6
Concentiation 63.6 m g/mL 64.2 m g/mL 64.8 m g/mL 64.0
mg/mL 64.9 m g/mL 64.9 m g/mL
Non-reduced Intact I gG: 96.9% Intact I gG: 96.6% Intact I gG: 96.2% Intact I
gG: 95.2% Intact I gG: 94.2% Intact I gG: 93.9%
and reduced Total IgG: 96.6% TotalIgG: 96.1% TotalI gG: 95.7% TotalIgG:
95.5% Tota 1 IgG: 93.9% TotalI gG: 94.1%
CE-SDS HC: 64.5% HC: 64.2% HC: 64.1% HC: 64.2% HC:
62.9% HC: 63.3%
W LC: 32.2% LC: 31.9% LC: 31.6% LC: 31.3% LC:31.1
A LC: 30.8 A
cm
t..1
SEC 97.4% Monomer 96.8% Monomer 96.9% Monomer 96.4% Monomer
96.1% Monomer 96.3% Monomer
2.0% Agge gate 2.4% Aggfe gate 2.5 A Aggregate 2.8% Aggregate
3.0% Aggregate 2.9 A Aggregate
picIEF p1=8.8 p I =8.9 p1=8.9 p1=8.9 pI
=8.9 pI =8.9
Conforms to Ref Conforms to Ref Conforms to Ref Conforms to Ref Conforms to
Ref Conforms to Ref
Std. No additional Std. No additional Std. No additional Std. No additional
Std. No additional Std. No additional
peaks seen. peaksseen. peaks seen. pea ks seen.
peaks seen. peaksseen.
Main peak = 55.9% Main peak= Main peak= Main peak= Main
peak= Main peak=
Acidic = 42.4% 56.8% 54.2% 53.5% 51.7%
50.5%
Basic =1.7% Acidic =41.2% Acidic =43.7% Acidic =44.3%
Acidic =46.3% Acidic =47.4%
Basic =2.0% Basic =2.1% Basic =2.2%
Basic =2.0% Basic =2.1%
it
Affinity
n
111% 136% 87% 99.7% 130%
97% 1.7.J.
Cl)
Biological
kµ.)
o
NP NP NP NP NP
88% ks.)
activity
kµ.)
O'
1-,
o
NP=not performed; picIEF
oc
.6.
1-,
17J.
to
Table 52 Stability Study: Data for Storage Conditions 25 C/60%RH
0
kµ.)
Timepoints (in months)
kµ.)
Test Initial 1 3
6
oc
Appearance Conforms Conforms Conforms
Confirms
No particulates observed No particulates
observed No particulates observed
pH 6.6 6.6 6.6
6.55
Concentration 63.6 mg/mL 63.9 m g/mL 64.7 mg/mL
63.6 m g/mL
Non-reduced Intact I gG:969% Intact IgG:949% Intact IgG:90.7%
Intact I gG:81.4 %
and reduced Total IgG: 96.6% Total IgG: 94.0% TotalI gG: 90.1%
TotalI gG: 84.9%
CE-SDS HC:64.5% HC:63.4% HC:62.0 %
HC: 60.5 (1/0
LC:32.2% LC:30.6% LC:28.1%
LC:24.4%
SEC 97.4% Monomer 96.2% Monomer 95.4% Monomer
93.3% Monomer
7`
2.0% Aggregate 2.8% Aggregate 3.3% Aggregate
4.5% Aggregate
icIEF p1=8.8 p I =8.9 pI = 8.9
pI = 8.8
Conforms to Reference Conforms to Reference
Conforms to Reference Conforms to Reference
Standard. No additional Standard. No additional
Standard. No additional Standard.No additional
peaks seen, peaks seen. peaks seen.
peaks seen.
Main peak =55.9% Main peak =48.6% Main peak =375%
Main peak = 25.3
Acidic = 42.4% Acidic = 49.2% Acidic = 60.2%
Acidic = 72.6%
Basic =1.7% Basic =2.2% Basic =2.3%
Basic =2.1%
Affinity
111% 123% 86%
115%
icIEF= Imaged capillary isoelectric focusing
17.J.
kµ.)
ks..)
kµ.)
oc
n
>
o
L.
r.,
o
-.4
to
174.
r.,
o
r.,
`.'
9'
. Table 53 ICH Stability Study: Data for Storage Conditions 2-8 C,
Upright
Timepoints (in months)
0
Test
kµ.)
Initial 1
3 6
kµ.)
t.).
Appearance Appearance conforms.
Appeamnce conforms. Appearance conforms. Appearancec onfoims. 1--,
--.1
pH
No particulatesobserved. No particulatesobserved.
No particulatesobserved. No particulatesobserved. oc
0.
!A
.0
6.6 6.5
6.5 6.5
Concentration 61 m g/mL 61mg/mL 61
mg/mL 61 mg/mL
Non-reducedCE-SDS IntactIgG: 95% Intact I
gG:95.4% Intact I gG:95.2% IntactIgG: 93%
ReducedCE-SDS Total IgG: 95%
TotalIgG:95.8% Totall gG:95.0% Total I gG: 94.0%
Heavy Chaim:63.8% Heavy Chain:64.4% Heavy Chain:63.7% Heavy
Chain:62.8%
Light Chain:31.6% Light Chain:31.4% Light-Chain:31.3% Light
Chain:31.6%
ca
c)
.-.1
SEC 98% Monomer 97.1 /o
Monomer 97.7% Monomer 95.8% Monomer
1
2% Aggregate 2.9% Aggregate 2.3%
Aggregate 3.9% Aggregate
icIEF pI = 8.9 pI = 8.9 pI
= 8.9 pI = 8.9
Main peak =55% Main peak =53 .6% Main peak=52.1% Main peak
=49.9%
Acidic = 43.1% Acidic = 44.5% Acidic = 45.9% Acidic =
48.2 /0
Basic =2.0% Basic =2.0%
Basic =1.9% Basic =1.9%
Affinity 111% 127%
95% 94%
Biolo gic a la ctivity NP NP NP
96%
Endotoxin <0.0004 EU/mg NP NP
NP
Sterility No growth,sterile NP
NP NP
ro
n
Subvisible particulates 210 p.m: 15.5particks per container; NP
NP NP
225 urn: Oparticlespercontainer
cp
kµ.)
Extra ctablevolume Confonns(9.3mL) NP'
NP' Conforms (9.1 mL)
ks..)
kµ.)
O'
c,
NP=not performed
cx
.6.
1...
n
>
o
L.
r.,
o
-.4
to
174.
r.,
o
r.,
`.'
9'
. Table 54 ICH Stability Study: Data for Storage Conditions 25 C/60% RH,
Upright
Timepoints (in months)
0
Test
kµ.)
Initial 1 3 6
kµ.)
t.).
Appearance Appeamnce conforms. Appearance conforms.
Appearance conforms. Appearance conforms. 1--,
--.1
No particulates observed. No particulates observed.
No particulates observed. No particulates
observed. 00
0.
!A
pH 6.6 6.5 6.5
6.5 .0
Concentration 61mg/mL 61 mg/mL 62 mg/mL
61 mg/mL
Non-reduced CE-SDS IntactIgG: 95% Intact IgG: 93.2% Intact I
gG: 88.1% Intact I gG: 82%
Reduced CE-SDS Total IgG: 95% Total IgG: 94.2% TotalIgG:
88.7% TotalIgG: 84%
Heavy Chain: 63.8% Heavy Chain: 64.0% Heavy
Chain: 61.5% Heavy Chain:59.5%
Light Chain: 31.6% Light Chain: 30.2% Light
Chain: 27.1% Light Chain: 24.5%
SEC 98% Monomer 96.5% Monomer 95.2%
Monomer 92.8% Monomer
(J.)
o 2% Aggregate 3.5%
Aggregate 4.8% Aggregate 3.7% Aggregate
00
icIEF pI = 8.9 pI = 8.9 pI =
8.9 p I = 8.9
Main peak =55%Acidic = Main peak =44.6%Acidic =
Main peak=33.9% Main peak = 25.1%
43.1% 53.2% Acidic= 63.9% Acidic= 73.0%
Basic =2.0% Basic =2.2% Basic
=2.2% Basic =1.9%
Affinity 149% 95% 91%
96%
Biological activity NP NP NP
78%
Endotoxin <0.0004 EU/mg
Sterility No growth, sterile
210 p.m: 15.5particles per
210 in: 12.0particles
container;
per container;
Subvisible particulates
It
225 gin: 0 paiticlesper
225 i.ttn : 0 particle sper n
17.J. container
container
Extractable volume Conforms (9.3 mL)
Conforms (9.0 mL) cp
i..)
o
ks..)
NP=not performed
k..)
O-
c,
oc
.6.
1...
WO 2022/178159
PCT/US2022/016841
Example 26: Results of Phase I Clinical Studies on Safety, PK, PD, and
Immunogenicity.
[00583] A phase I clinical study was completed to assess the safety, PK, PD,
and other
parameters for the anti-TL1A antibody (e.g. A219). The Phase I clinical study
tested double-
blind, randomized, placebo-controlled, single dose followed by multiple dose.
In the Single
Ascending Dose (SAD) cohort, the anti-TL1A antibody (e.g A219) was tested in a
total of 46
subjects with 3 to 1 randomization (35 to 11) in each dosing cohort. 6 cohorts
(e.g. 6 dose
levels) were tested for the SAD, which were 5 mg, 25 mg, 100 mg, 300 mg, 600
mg, and
1000 mg, with a follow-up period of 14 weeks. In the Multiple Ascending Dose
(MAD)
study, the anti-TL1A antibody (e.g. A219) was tested in 23 subjects with 3 to
1
randomization (17 to 6) in each dosing cohort. In the MAD study, all subjects
received 3
doses at days 1, 15, and 29. 3 cohorts (dose levels) were tested for the MAD
study, which
were 50 mg, 200 mg, 500 mg, with a follow-up period of 18 weeks. The phase I
clinical
study evaluated the safety and tolerability, pharmacokinetics (PK),
immunogenicity (e.g., by
evaluating the anti-drug antibodies, ADA), and pharmacodynamic (PD) markers of
the anti-
'TL1A antibody (e.g. A219).
[00584] 68 out of the 69(98.5%) subjects completed the study and follow-up
period, with
one patient completed up to Week 8 in the 200 mg MAD but lost to follow-up. No
serious
adverse events (SAE) was observed in the clinical study. Neither drug-related
infusion
reactions nor drug-related extension in infusion time was seen during the
study (with 30-minute
infusions of up to 1000mg). No clinically significant changes were reported in
physical exam,
lab values, electrocardiogram, or vital signs.
[00585] All adverse events (AEs) assessed as related to study drug were mild.
Exemplary
mild AEs reported in the SAD study include 1 report of somnolence in the 35
subjects tested
with A219 (at the 600 mg dose) and 1 report of headache in the 11 subject
placebo group.
Exemplary mild AEs reported in the MAD study include: 1 report of diarrhea in
the 17
subjects tested with A219, 1 report of diarrhea in the 6 subject placebo
group, 1 report of
somnolence in the 17 subjects tested with A219, 1 report of dizziness in the
17 subjects tested
with A219, and 1 report of headache in the 11 subject placebo group.
[00586] Therefore, the anti-TL1A antibody (e.g. A219) has favorable safety and
tolerability.
[00587] Various PK parameters were determined and shown in FIGS. 27A and 27B,
and
Tables 55-59.
- 309 -
CA 03207817 2023- 8-8
9
to
Table 55 Summary of Serum A219 Pharmacoldnetic Parameters Following Single
Doses of A219 Administered as IV Infusion (SAD)
Treatment
0
Pha rmaco kinetic
Parameters A
AUCIast (tg*hillnL) 95.61 (79.7) [n=6] 1509 (33.1) [n=5]
10680 (16.9) [n=6] 35040 (22.8) [n=6] 72340 (24.4) [n=6]
135200 (12.5) [n=6]
oo
AUC14 (ttg*hr/mL) 120.6 (51.4) [n=6] 1246 (21.9) [n=5]
6080 (16.9) [n=6] 17200 (8.4) [11=6] 34940 (11.2) [n=6] 60130
(11.5) [11=61
AUC. (ug*hr/mL) 153.0 (63.4) [11=61 1713 (33.0) [n=5]
11170 (13.9) [n=6] 35360 (23.6) [n=6] 73290 (25.6) [n=6]
137500 (12.8) [n=6]
AUC% extmp(, ) 33.88+20837 [n=6] 11.41+ 10.050 [n=5]
4.297+5.5045 [11=6] 0.9035 +1.2359 [n=6] 1.296 +1.2698 [n=6] 1.730
+1.4655 [n=6]
C., (pg/mL) 0.9647 (43.7) [11=6] 9.447 (14.8) [n=5]
39.89 (16.2) [n=6] 1181 (18.3) [n=6] 219.7 (10.9) [n=6] 379.2
(20.6) [n=6]
(hr) 0.759 (0.50, 2.00) [11=611.000 (0.52,2.00) [n=5]
0.509 (0.50, 1.00) [n=6] 0.759 (0.50, 1.00) [n=6] 1.000 (0.52, 12.00)
0.750 (0.50,6.00) [n=6]
[n=6]
Kei (1/hr) 0.005049+0.0019135 0.004031+0.0010395 0.002710
+0.00043788 0.002543+0.00067609 0.002588+0.0010459 0.002017+0.00061249
[11-61 [n=5] [n=6] [n=6]
[n=6] [11-61
(hr) 151.4+46.474 [n=6] 181.4+46.482 [n=5]
262.4+49.651 [n=6] 296.1+10939 [n=6] 306.5+116.50 [n=6]
369.7+108.15 [n=6]
CL (L/hr) 37.48 +21.666 [n=6] 15.17+ 4.3784 [n=5]
9.024+1.3063 [n=6] 8.676 +1.9984 [n=6] 8.406 +2.1096 [n=6]
7.322+ 1.0102 [n=6]
V, (L) 7.142+2.1467 [n=6]
3.762+0.64753 [n=5] 3.427+0.82422 [n=6]
3.555+0.88397 [n=6] 3.485 +0.85549 [n=6] 3.846+1.0698 [n=6]
DN AUCiast 19.12 (79.7) [n=6] 60.37 (33.1) [n=5]
106.8 (16.9) [n=6] 116.8 (22.8) [n=6] 120.6 (24.4) [n=6] 135.2
(12.5) [n=6]
(ttg*hr/mL/mg)
DN AUCt4 2.547 (1094.4) [n=6] 16.79 (602.2) [n=5]
53.11(881.3) [n=6] 150.2 (760.8) [n=6] 3416 (618.7) [n=6]
104.6 (98.2) [n=6]
(ttg*hr/mL/mg)
DN AUC. 30.60 (63.4) [n=6] 68.52 (33.0) [n=5]
111.7 (13.9) [n=6] 117.9 (23.6) [n=6] 122.1 (25.6) [n=6] 137.5
(12.8) [n=6]
(ttg*hr/mL/mg)
DN Cma x (ktWmL/mg) 0.1929 (43.7) [n=6] 0.3779 (14.8) [n=5]
0.3989 (16.2) [n=6] 0.3940 (18.3) [n=6] 0.3662 (10.9) [n=6]
0.3792 (20.6) [n=6]
A single dose of the treatments was administered as an IV infusion over 30
minutes atIIour 0 on Day 1.
Treatment: A = 5 mg A219; B = 25 mg A219;C = 100 mgA219;D = 300 mgA219;E= 600
mgA219;F = 1000 mgA219
AUCs and C., are presented as geometric mean and geometric CV%.
Tmax values are presented as median (minimum, maximum).
Other parameters are presented as arithmetic mean (1 SD).
11)
00
WO 2022/178159
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Table 56 Summary of Serum A2 19 Pharmacokinetic Parameters Following Multiple
Doses
of A2 19 Q2W Administered as IV Infusion - Day 1 (MAD)
Treatment
Pharmacokinetic
Parameters
AUCtasi (iehr/mL) 2640 (14.2) [11=6] 11600 (12.3)
[11=6] 30760 (16.6) [n=5]
AUCH (n.g*hr/mL) 2640 (14.2) [n=6] 11610 (12.3)
[n=6] 30770 (16.6) [n=5]
Cmax (]tgimL) 17.92(12.4) [n=6] 73.77 (15.7)
[n=6] 199.0 (17.6) [n=5]
T(hr) 0.759 (0.52, 1.12) [n=6]
1.500 (1.00, 6.00) [n=6] 1.000 (1.00, 1.05) [n=5]
Ctrough ( WnaL) 4.070 +1.2370 [n=6] 22.55 +3.4233
in=61 59.40 + 8.6232 [n=5]
Kei (1/hr) 0.003658 + 0.00137101(1=6] 0.002395 +0.00033531
[n=6] 0.002401 +0.00034915 [n=5]
11/2 (hr) 211.3 +71.445 [n=6] 293.6+35.9851n61
293.5 + 41.107 [n=5]
DN A U Cias] (p..g*hr/mL/mg) 52.80(14.2) [n=6] 58.01 (12.3)
[n=6] 61.52 (16.6) [n=5]
DN AUCH (pg*hr/mL/mg) 22.67 (139.1) [n=6] 85.51
(167.1) [n=6] 106.6 (59.6) [n=5]
DN Cmtx (p.g/rnL/ing) 0.3584 (12.4) [n=6] 0.3688
(15.7) [n=6] 0.3980 (17.6) [n=5]
Multiple doses of the treatments were administered as an IV infusion over 30
minutes at Hour 0 on Days 1,15, and 29.
Treatment: G = 50 mg A2 19 Q2W; H = 200 mg A219 Q2W; 1= 500 mg A2 19 Q2W
AUCs and C. are presented as geometric mean and geometric CV%.
T. values are presented as median (minimum, maximum).
Other parameters are presented as arithmetic mean ( SD).
Table 57 Summary of Serum A2 19 Pharmacokinetic Parameters Following Multiple
Doses
of A2 19 Q2W Administered as IV Infusion - Day 15 (MAD)
Treatment
Pharmacokinetic
Parameters
AUC]. ( g*hr/mL) 3407 (29.1) [n=6] 19810 (15.9) [n=6]
50020 (15.4) [n=5]
Cmax,ss (lugin114 23.37 (18.0) [n=6] 99.02 (15.9)1(1=6]
255.7 (17.6) [n=5]
Cmin,ss (11g/mW 5.215+3.0633 [n=6]
43.52 + 6.9761 [n=6] 117.8+50.064 [n=5]
Cav,ss 41g/111W 10.46 +2.5815 [n=6]
59.58+ 9.5902 [n=6] 150.3 + 23.364 [n=5]
Ctrough (pg/mL) 5.215+3.0633 [n=6]
43.52 + 6.9761 [n=6] 99.56 18.158 [n=5]
Tmax,ss (hr) 2.067 (0.52, 6.00) [n=6]
0.534 (0.50, 6.08) [n=6] 2.000 (0.60,2.40) [n=5]
Kei (1/hr)
0.004610 +0.0024974 [n=6[ 0.001823 + 0.00024889 [n=6] 0.002296 0.00054397
[n=5]
11/2 (hr) 191.3 +95.015 [n=6]
386.4 55.219[n6] 313.6 +62.774 [1]=5]
CLss (L/hr) 15.23 +4.9675 [n=6]
10.20 1.5635 [n=6] 10.09+1.5138 [n=5]
Vss (L) 3.790 +1.3556 [n=6]
5.675 + 1.1080 [n=6] 4.604 1.3739 [n=5]
DN AUCia, (ug*hrinaL) 68.15 (29.1) [n=6] 99.05 (15.9)1(1=6]
100.0 (15.4) [n=5]
DN Cmax,ss (IlgimL) 0.4674 (18.0) [n=6] 0.4951 (15.9)
[n=6] 0.5115 (17.6) 1n=51
Rac,AUC 1.315 +0.29105 [n=6]
1.717+0.20859 [n=6] 1.630+0.12819 [n=5]
Rac,Cmax 1.309 + 0.12730 [n=6]
1.344 + 0.069527 [n=6] 1.288+0.091554 [n=5]
RP-T 7.114+5.4916 [n=6] 2.320
0.33489 [n=6] 2.413 +0.78742 [n=5]
%FLU C 188.8+71.269 [n=6]
95.92 + 22.110 [n=6] 94.78+33.105 [11+5]
Multiple doses of the treatments were administered as an IV infusion over 30
minutes at Hour 0 on Days 1, 15, and
29.
Treatment: C1 = 50 mg A219 Q2W; H = 200 mg A219 (NW; I = 500 mg A219 Q2W
AUCs and Cm,. are presented as geometric mean and geometric CV%.
Tmax values are presented as median (minimum, maximum).
Other parameters are presented as arithmetic mean (+ SD).
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Table 58 Summary of Serum A219 Pharrnacokinetic Parameters Following Multiple
Doses
of A219 Q2W Administered as IV Infusion - Day 29 (MAD)
Treatment
Pharmacokinetic
Parameters
AUCteu (pg*hr/mL) 3148 (51.4) [n=6] 23740 (11.9) [n=6]
57430 (10.6) [n=5]
C.,ss (111:0111-) 23.08 (19.5) [n=6] 119.5 (11.5) [n=6]
300.1 (13.9) [n=5]
Cmin,ss( OIL) 9.190 4.9563 [n=61 66.30 6.8972 [n=6]
159.4 15.821 [n=5]
Cav,ss (tig/mL) 10.22+4.1844 [0=61 71.08+8.5764 [n=6]
171.7 +18.425 [n=5]
Cvough (1.tWinL) 0.6997 +0.63205 [n=6] 16.93 +6.9592 [n=6]
47.83 +10.898 [n=5]
Tinax,ss (lir) 1.325 (0.52.5.95) [n=6] 2.000 (0.50,
6.13) [n=6] 2.000 (0.50, 6.00) [n=5]
Kei (1/hr) 0.003935 + 0.0031363 [n=6] 0.001901 +0.00071255
[n=6] 0.001677 + 0.00067543 [n=5]
t1/2 (hr) 272.6 195.15 [n=6] 398.5 +112.66 [n=6]
459.2 +148.22 [n=5]
CL ss (L/hr) 17.65 +9.6843 [n=6] 8.473 +0.98033
[n=6] 8.744+0.90047 [n=5]
V( L) 5.427 2.4446 [n=6] 4.788+1.1813 [n=6]
5.816 2.1556 [n=5]
DN AUCtau 62.97 (51.4) [n=6] 118.7 (11.9) [n=6]
114.9 (10.6) [n=5]
(tig*hr/mL)
DN Curax,ss (m/mL) 0.4616 (19.5) [n=6] 0.5975 (11.5) [n=6]
0.6002 (13.9) [n=5]
Ra c,A15C 1.278 0.51418[n6] 2.050 +0.14354
[n=6] 1.872+0.16208[n5]
Rac,cmax 1.297 +0.16900 [n=6] 1.630 +0.19500
[n=6] 1.511 + 0.10221 [n=5]
RP-T 3.381 +1.9300 [n=6] 1.814 +0.11010
[n=6] 1.897+0.18838 [n=5]
%FLUC 174.3+107.19 [n=6] 75.58+5.6244 [n=6]
83.10+15.890 [n=5]
Multiple doses of the treatments were administered as an IV infusion over 30
minutes at Hour 0 on Days 1, 15,
and 29.
Treatment: G = 50 mg A219 Q2W; H = 200 mg A219 Q2W; I = 500 mg A219 Q2W
AUCs and Cmax are presented as geometric mean and geometric CV%.
T.values are presented as median (minimum, maximum).
Other parameters are presented as arithmetic mean (T SD).
Table 59 Steady-State Assessment of Serum A219 Ctrough Values Following
Multiple Doses
of A219 Q2W Administered as IV Infusion (MAD)
Treatment Day Geometric LS Mean p-
value
Ctiough Day 1 3.897 0.0952
4.180 0.0075
Cueeen Day 2 0.189
Ctrough Day 1 22.34 0.4891
43.08 0.0004
Ctrough Day 2 14.88
Ctrough Day 1 58.91 0.1052
98.26 <10.0001
Ctrough Day 2 46.84
Multiple doses of the treatments were administered as an IV infusion over 30
minutes at
Hour 0 on Days 1, 15, and 29.
Treatment: G = 50 mg A219 Q2W; H = 200 mg A219 Q2W; I = 500 mg A219 Q2W
Concentrations were ln-transformedprior to analysis.
Geometric least-squares means (LSMs) were obtained by taking the exponential
of the
LSMs from ANOVA.
p-value corresponds to the Helmert contrast, i.e., the comparison of that day
versus the
average of the remaining day s.
The Cuoughvalues on Days 1,15, and 29 correspond to the predose on Days 15,
and 29, as
well as the derived Cgouen following dosing on Day 29, respectively.
. = Value missing or not reportable.
1005881 Results shown in FIGS. 27A and 27B, and Tables 55-59 demonstrate that
the PK
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of the anti-TLIA antibody (e.g. A219) meets the PK performance standards for a
therapeutic
antibody and supports the phase 2 dosing regimen discussed in Section 5
(Examples). The
half-life after a dose of 500 mg every other week is about 19 days. Dose
proportional
exposure at doses greater than or equal to 100 mg was observed in the PK
profile.
1005891 Furthermore, target engagement was assessed by determining the soluble
TLIA
concentration in the serum of the subjects in the clinical studies. The anti-
TL1A antibody
A219 provided herein demonstrated dose-dependent, robust, sustained target
engagement as
shown in FIGS. 28A and 28B. Target engagement as determined by the increase in
the
soluble TL1A in serum maximized at 200 mg A219 Q2W at about 45,000 pg/mL sTL1A
(FIG. 28B). Such a target engagement is more than 4 fold higher than observed
in the control
reference anti-TL1A antibody that only binds to trimeric TL1A (control
reference antibody
sequence, light chain SEQ ID NO: 382 and heavy chain SEQ ID NO: 383) (see
Banfield C, el
al. Br J Clin Pharmacol. 2020;86:812-824; Danese S, et al. Clin Gastroenterol
Hepatol. 2021
Jun 11;S1542-3565(21)00614-5; Danese S, etal. Clin Gastroenterol Hepatol. 2021
Nov;19(11):2324-2332.e6). Therefore, the anti-TL1A antibody provided herein
that binds to
both monomeric and trim eric TL1 A provide superior target engagement over the
anti-TL1 A
antibody that binds to only trimeric TL1A.
1005901 Additionally, immunogenicity of the anti-TL1A antibody is assessed by
determining the anti-drug antibody (ADA). At clinically relevant dose (1000 mg
SAD, 200
mg and 500 mg MAD), immunogenicity rate was no more than 20%. In contrast, the
reported immunogenicity (e.g., ADA positivity) rate for the control reference
anti-TL1A
antibody (light chain SEQ ID NO: 382 and heavy chain SEQ ID NO: 383) was over
80% at
similar doses in both normal healthy volunteer and UC patients (see Banfield
C, et al. Br J
Clin Pharmacol. 2020;86:812-824; Danese S, et al. Clin Gastroenterol Hepatol.
2021 Jun
11; S1542-3565(21)00614-5; Danese S, et al. Clin Gastroenterol Hepatol. 2021
Nov;19(11):2324-2332.e6). ADA titers observed in the clinical trial were
inversely
proportional to A219 exposure and ADA positivity only occurred at low A219
concentrations.
1005911 To further evaluate the potential impact of ADA, neutralizing antibody
was also
determined in the phase I trial. Neutralizing antibody rate at clinically
relevant dose was
uncommon and was observed only in 1 out of 17 subjects (6%) across the
clinically relevant
dose groups (1000 mg SAD, 200 mg and 500 mg MAD). Immunogenicity observed in
the
phase I trial was not clinically relevant in that (1) ADA did not impact
safety because there
were no report of infusion reaction throughout the study, (2) ADA did not
impact clearance
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of A219 in the population PK model, and (3) ADA did not impact target
engagement because
there was no apparent impact on sTL1A level as shown in FIGS. 28A and 28B.
1005921 In summary, the anti-TL1A antibody provided herein has favorable
safety and
tolerability; PK of the anti-TL1A antibody provided herein meets performance
standards and
supports phase 2 dosing regimen; the anti-TL1A antibody provided herein
neutralizes both
active trimeric TL1A and inactive monomeric TL1A, leading to increased and
sustained
target engagement and potentially to more effective reduction of active TL1A
in tissues; the
anti-TL1A antibody provided herein do not trigger immunogenicity that may
adversely
impact its therapeutic efficacy.
Example 27: Further validation of physiologically based pharmacokinetic (PBPK)
modeling and population pharmacokinetic modeling (popPK) with the phase I
clinical
trial results.
1005931 Based on the PK, PD, and TL1A concentration data from the subjects of
the phase
I clinical trial, further PBPK modeling, popPK modeling, and validation of the
models were
conducted. As further described above (e.g. in this Section 5 (Examples)), the
key
mechanisms included in the PBPK models include: central, peripheral, and
diseased ti ssue
(e.g. gut) compartment; TL1A synthesis and clearance, interchange between
trimer and
monomer states; upregulated TL1A synthesis in disease gut tissue of IBD
patients; binding
by A219 to both monomer and trimer TL and binding a control reference antibody
only to
trimer TL1A; administration, distribution, non-specific elimination, and
membrane TL
mediated target mediated drug disposition for the anti-TL1A antibodies;
distribution and
clearance of bound complexes. The inputs to the PBPK model include: (1) the
anti-TL1A
antibody provided herein binds to both TL monomer and trimer, whereas the
control
reference antibody (light chain SEQ ID NO: 382 and heavy chain SEQ ID NO: 383)
binds
only to TL1A trimer; (2) TL1A is synthesized systemically in the peripheral
compartment in
healthy subjects and in inflamed gut tissue, and the elevated tissue
expression of TL1A is
caused by increased synthesis of TL1A within the diseased tissue; (3) trimer
TL1A and
monomer TL1A interchange at a rapid equilibrium, resulting in a fixed steady
state ratio of
monomer to trimer; (4) TL1A trimers/monomers bound to drug do not change
forms; (5) the
anti-TL1A antibody binds trimer or monomer with the same effective Kd in a
single binding
event; (6) free TL1A monomer and trimer clear at different rates; (7) antibody
bound TL1A
monomer and antibody bound TL1A trimer clear at the same rate; (8) antibody
bound TL1A
monomer and antibody bound TL1A trimer distribute the same as the antibody;
antibody
bound to membrane TL1A internalizes at the same rate as membrane TL1A. The
exemplary
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values for the various parameters for the anti-TL1A antibodies are described
in Table 60.
Table 60. Parameters used in the modeling (drug¨anti-TL1A antibody)
Value Description
3 Circulation volume
13 Systemic interstitial volume
0.27 (6.6 h) Half-life of free TL1A trimer
0.028 (40 min) Half-life of free TL1A monomer
0.6 Mass fraction of trimer
1.9 Distribution timescale for TL1A into the
peripheral compartment
1 Partition coefficient of TL1A into the
peripheral compartment
0.1 Total membrane bound TL1A (membrane
T1VIDD)
6 Internalization rate of free
receptor
144 Drug molecular weight (for dosing)
2.5 Absorption half-time (typical mAb) for SC
dosing
0.5 Bioavailability for SC dosing
0.05 Drug binding affinity to TL1A
1 Ability of drug to bind TL1A monomer
21 Linear elimination half-life of drug
35 Distribution timescale for drug into
peripheral compartment
0.2 Partition coefficient of drug into
peripheral compartment
35 Distribution timescale for drug: TL1A complex
into peripheral
compartment
0.2 Partition coefficient of drug: TL1A complex
into the peripheral
compartment
1.1 Linear elimination half-life of drug
:trimer complex
1.1 Linear elimination half-life of
drug:monomercomplex
225 Baseline concentration oftotal TL1A
12.95 Systemic interstitial volume minus diseased
gut volume
0.05 Diseased gut volume assuming 50% colon
involvement with 100 mL
colon interstitial volume (Shah and Betts)
20 Fold molar increase in TL1A synthesis rate in
the diseased guttissue
compared to the peripheral synthesis rate
35 Distribution timescale for drug into gut
compartment
0.04 Partition coefficient of drug into gut
compartment
35 Distribution timescale for drug :TL1A complex
into gut compartment
0.04 Partition coefficient of drug: TL1A complex into
the gut compartment
225 Baseline concentration oftotal TL1A
(disease)
1005941 For validation of the model, the model was fit to the SAD data and
benchmarked
to Q2W data of the phase I clinical trial with A219. As shown in FIGS. 29A and
29B, the
model fitted to single ascending dose data of A219 with reasonable agreement.
Furthermore,
as shown in FIGS. 29C and 29D, the model was able to capture multiple
ascending dose data
of A219 without additional fitting, indicating the consistency and robustness
of the model.
Similarly and without additional fitting, the model captured the data of a
control reference
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antibody that binds only to TL1A trimer (light chain SEQ ID NO: 382 and heavy
chain SEQ
ID NO: 383) with regard to (1) phase I single ascending dose data (FIGS. 29E
and 29F), (2)
phase I multiple ascending dose data (FIGS. 29G and 29H), and (3) phase II
data on PK &
total sTL1A levels (FIGS. 291 and 29J) (Banfield C, et al. Br J Clin
Pharmacol. 2020;86:812-
824. Danese S, et al.. :Clin Gastroenterol Hepatol. 2021 Nov;19(11):2324-
2332.e6, Hassan-
Zahraee M, etal. Inflammatory Bowel Diseases 2021, XX, 1-13). The IBD specific
parameters were then calibrated to capture free tissue TL 1 A levels in the
gut (FIG. 29K) as
observed with the control reference antibody (light chain SEQ ID NO: 382 and
heavy chain
SEQ ID NO: 383) in clinical trials. As such the model was validated with the
clinical trial
data.
1005951 This validated model can be used to determine the dose to reduce the
free TL1A
concentration in the patient's diseased tissue to below the TL1A concentration
of the
corresponding tissue in a healthy subject, similar to that described above in
Example 20 and
21. FIG. 30A and 30B show examples of such doses determined from the validated
model
that can bring the free TL1A concentration in the patient's diseased tissue to
below the TL1A
concentration of the corresponding tissue in a healthy subject (IV 4x= 1000 mg
loading
dose, 3 500 mg on days 14,42, 70; SC dosing 240 mg Q1W or Q2W).
1005961 The validated model also confirmed that anti-TL1A antibodies that bind
to both
TL1A monomer and trimer can engage more TL1A in circulation and result in
greater
reduction of TL1A in diseased tissue than anti-TL1A antibodies that only bind
to TL1A
timer. In a head-to-head comparison in the validated model, anti-TL1A
antibodies that bind
to both TL1A monomer and timer engaged more TL1A in circulation than anti-TL1A
antibodies that only bind to TL1A trimer as shown in FIG. 30C, with the
circulation TL1A
accumulation ratio determined to be 3.5 fold. In a head-to-head comparison in
the validated
model, anti-TL1A antibodies that bind to both TL1A monomer and trimer also
resulted in
higher percentage of TL1A reduction of TL1A in diseased tissue (about 100%
reduction from
day 0) when compared to anti-TL1A antibodies that only bind to TL1A trimer, as
shown in
FIG. 30D. Because the diseased tissue of IBD patients often produces 20,30,
40,50, 60,70,
or even 100 fold more TL1A as shown in Examples 20 and 21 above, a few
percentage point
of residual TL1A production in the diseased tissue of the patients can still
be a pathological
TL1A concentration.
1005971 Similarly, popPK model was further fitted and validated
with the phase I clinical
trial data. Briefly, 2 compartment popPK Model for A219 with linear and non-
linear
elimination (target-mediated drug disposition) was established as shown in
FIG. 31A and as
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described above. No covariates were found to have a clinically relevant effect
on PK
parameters. The popPK model fitted the phase I clinical trial data well and
reliably predicted
A219 and TLIA concentration data in the tested population, as shown in FIGS.
31B-31E.
Further, there was no apparent bias between the predicted and observed A219
and TL1A
concentrations (FIGS. 31B-31E).
1005981 Having validated the popPK model, the popPK model was used to
determine
A219 and TL IA concentrations under various dosing regimen. The validated
popPK model
confirmed the dose to achieve the levels of anti-TLIA antibody concentration
and
engagement of TL I A in the serum (total soluble TL I A concentration in
circulation) in order
to lower the TLIA concentration in the diseased tissue to below that of a
healthy subject, as
shown in FIGS. 3 2A-3 2H.
Table 9B. Fe and Constant Regions
SEQ ID NO: 319 Light Chain Constant
RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNEYPREAKVQWKVDNALQSGNSQESVTEQDS
KDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO: 320 IgG1 Constant
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SG
LYSLS SVVTVPSS SLGTQTYICNYNHKPSNTKVDKKVEPKS CDKTHTCPPCPAPELLGGPSV
FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK
NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG
NVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO: 321 IgG1 Constant
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SG
LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSV
FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTK
NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG
NVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO: 322 IgG1 Constant
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SG
LYSLS SVVTVPSS SLGTQTYICNVNHKPSNTKVDKKVEPKS CDKTHTCPPCPAPELLGGPSV
FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP REP QVYTLPPSREE MTK
NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTIPPVLDSDGSFFLYSKLTVDKSRWQQG
NVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO: 323 Fcl (L235E)
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SG
LYSLS SVVTVPSS SLGTQTYICNYNHKPSNTKVDKKVEPKS CDKTHTCPPCPAPELEGGPSV
FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK
NQVSLTCLVKGFYPSDIAVEWESNGQPENNYK FIPPVLDSDGSFELYSKLTVDKSRWQQG
NVESCSVMHEALHNHYTQKSLSLSPCK
SEQ ID NO: 324 Fc2 (L235E)
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ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG
LYS LS SVVTVP S S SLGTQTYICNVNHKP SNTKVDKRVEPKS CDKTHTCPP CPAP ELE GGPS V
F LF P P KP K D TLMI S RTP E VTCVVVDV S HE DP EVKFNVVYVD GVE VHNAKTKPRE EQ YN
S TY
RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTK
NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKFIPPVLDSDGSFFLYSKLTVDKSRWQQG
NVF S C S VMHE A LHNHY TQ K S LS LS P GK
SEQ ID NO: 325 Fc3 (L235E)
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG
LYS LS SVVTVP S S SLGTQTYICNVNHKPSNTKVDKKVEPKS CDKTHTCPPCPAPELEGGPSV
FLFPPKPKD'TLMISR'TPEVTCVVVDVSHEDPEVKFNVVYVDGVEVHNAKTKPREEQYNSTY
RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTK
NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKI.IPPVLDSDGSFFLYSKLTVDKSRWQQG
NVF S C S VMHE A LHNHY TQ K S LS LS P GK
SEQ ID NO: 326 Fc4 (L234A, L235A)
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG
LYS LS SVVTVP S S SLGTQTYICNVNHKPSN'TKVDK KVEPKS CDK THTCPP CP APE A AGGP S
VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST
YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELT
KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK l'IPPVLDSDGSFFLYSKLTVDKSRWQQ
GNVF SC S VMHE ALHNHYTQ K S LS L S P GK
SEQ ID NO: 327 Fc5 (L234A, L235A)
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG
LY S LS SVVTVP S S SLGTQTYICNVNHKPSNTKVDKRVEPKS CDKTHTCP P CP AP EAAGGPS
VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST
YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMT
KN QV SLTCLVKGFYP SDIAVEWESNGQPENN Y KTTPPVLDSDGSFFLY SKLTVDKSRWQQ
GNVF SC S VMHE ALHNHYTQ K S LS L S P GK
SEQ ID NO: 328 Fc6 (L234A, L235A)
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG
LYS LS SVVTVP S S SLGTQTYICNVNHKPSNTKVDKKVEPKS CDKTHTCPPCPAPEAAGGP S
VF LF P P KP KD TLMI S RTP E VTCVVVDV SHE D P EVKFNWYVD GVE VHNAKTKP RE EQYNS
T
YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMT
KNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKIIPPVLDSDGSFFLYSKLTVDKSRWQQ
GNVF S C S VMHE ALHNHYTQ K S LS L S P GK
SEQ ID NO: 329 Fc7 (L234A, L235A, G237A)
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG
LYS LS SVVTVP S S SLGTQTYICNVNHKPSNTKVDKKVEPKS CDKTHTCPPCPAPEAAGAP S
VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST
YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELT
KNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKI.IPPVLDSDGSFFLYSKLTVDKSRWQQ
GNVF S C S VMHE ALHNHYTQ K S LS L S P GK
SEQ ID NO: 330 Fc8 (L234A, L235A, G237A)
AS TKGP SVFPLAP S SKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS GVHTFPAVLQS SG
LY S LS SVVTVP S S SLGTQTYICNVNHKPSNTKVDKRVEPKS CDKTHTCP P CP AP EAAGAP S
VFLFPPKPKDTLMISRTPE VTCV V VDV SHEDPEVKFN WY VDGVE VHNAKTKPREEQY N ST
YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMT
KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK IIPPVLDSDGSFFLYSKLTVDKSRWQQ
GNVF S CS VMHE ALHNHYTQKS LS LSPG
SEQ ID NO: 331 Fc9 (L234A, L235A, G237A)
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG
LYS LS SVVTVP S S SLGTQTYICNVNHKPSNTKVDKKVEPKS CDK THTCPP CP APE A AGAP S
VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST
YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMT
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KNQVSLTCLVKGFYP SDIAVEWE SNGQPENNYK I 'I PP VLD S DGSFF LY SKLTVDKSRWQ Q
GNVF S C S VMHEALHNHYTQKS L S LS P G
SEQ ID NO: 332 Fc10 (L234A, L235A, P329G)
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG
LY S LS SVVTVP S S SLGTQTYICNVNHKPSNTKVDKKVEPKS CDKTHTCPPCPAPEAAGGP S
VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK1KPREEQYNST
YRVVSVLTVLHQDWLNGKEYKCKV SNK A LGAPIEKTT S K A KGQPREPQ VYTLPP SRDELT
KNQVSLTCLVKGFYP SDIAVEWE SNGQPENNYK 1 ' I PP V LD SDGSFFLYSKLTVDKSRWQQ
GNVF S C S VMHEALHNHYTQKS LS LS P GK
SEQ ID NO: 333 Fc 11 (L234A, L235A, P329G)
ASTKGP SVFPLAP S S KS TS GGTAALGCLVKDYF PE PVTV SWNS GALTS GVHTFPAVLQ S SG
LY S LS SVVTVP S S S LGTQ TYI CNVNHK P SNTKVDKRVE P KS CDKTHTCPPCPAPEAAGGPS
VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST
YRVV S VLTVLHQ DWLNGKEYKCKV SNKALGAP1E KIT S KAKGQ PRE PQVYTLPP S REE MT
KNQVSLTCLVKGFYP SDIAVEWE SNGQPENNYK I 'I PP VLD S DGSFF LY SKLTVDKSRWQ Q
GNVF S C S VMHE A LHNHYTQK S LS LS P GK
SEQ ID NO: 334 Fc12 (L234A, L235A, P329G)
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG
LY S LS SVVTVP S S SLGTQTYICNVNHKPSNTKVDKKVEPKS CDKTHTCPPCPAPEAAGGP S
VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST
YRVV S VLTVLHQ DWLNGKEYKCKV SNKALGAP1E KIT S KAKGQ P RE PQVYTLPP S REE MT
KNQVSLTCLVKGFYP SDIAVEWE SNGQPENNYK I 'I PP VLD S DGSFF LY SKLTVDKSRWQ Q
GNVF S C S VMHEALHNHYTQKS LS LS P GK
SEQ ID NO: 335 Fc13 (L234F, L235E, P33 1S)
ASTKGP SVFPLAP S S KS TS GGTAALGCLVKDYF PE PVTV SWNS GALTS GVHTFPAVLQ S SG
LY S LS S V VTVP S S SLGTQTYICN VNHKPSNTKVDKKVEPKS CDKTHTCPPCPAPEFEGGPS V
FLF P PKPKDTLMI S RTP EVTCVVVDV S HE DP EVKFNWYVD GVEVHNAKTKPRE EQYN S TY
RVVSVLTVLHQDWLNGKEYKCKVSNKALPA SIEKTISKAKGQPREPQVYTLPPSRDELTK
NQVSLTCLVKGFYP SDIAVEWE SNGQPENNYK 1 IPPVLDSDGSFFLYSKLTVDKSRWQQG
NVFS C S VMHEALHNHYTQ KS LS LS P GK
SEQ ID NO: 336 Fc14 (L234F, L235E, P33 1S)
A S'TKGP SVFPLA PS SK STS GGTA A LGCLVKDYFPEPVTVSWN SGALTS GVHTFP AVLQS SG
LY S LS SVVTVP S S S LGTQ TYI CNVNHKP SNTKVDK RVE P KS CDKTHTCPP CPAP EFEGGPS
V
FLF P PKPKDTLMI S RTP EVTCVVVDV S HE DP EVKFNVVYVD GVEVHNAKTKPRE EQYN S TY
RVVSVLTVLHQDWLNGKEYKCKVSNKALPA SIEKTISKAKGQPREPQVYTLPPSREEMTK
NQVSLTCLVKGFYP SDIAVEWE SNGQPENNYK IIPPVLDSDGSFFLYSKLTVDKSRWQQG
NVFS C S VMHEALHNHYTQ KS LS LS P GK
SEQ ID NO: 337 Fc15 (L234F, L235E, P33 IS)
ASTKGP S VFPLAP S S KS TSGGTAALGCLVKDYFPEPV TV SW N SGALTSGVHTFPAVLQS SG
LYS LS SVVTVP S S SLGTQTYICNVNHKPSNTKVDKKVEPKS CDKTHTCPP CPAPE FEG GPS V
FLF PP KP KDTLMI S R'TPEVTCVVVDV SHE DP EVKFNWYVDGVEVHNAKTKPRE EQYN S TY
RVVSVLTVLHQDWLNGKEYKCKVSNKALPA SIEK'TTSKAKGQPREPQVYTLPPSREEMTK
NQVSLTCLVKGFYPSDIAVEWE SNGQPENNYK I PPVLD SDGSFFLYSKLTVDKSRWQQG
NVFS C S VMHEALHNHYTQ KS LS LS P GK
SEQ ID NO: 338 Fc16 (L234A, L235E, G237A)
ASTKGP SVFPLAP SS KS TS GGTAALGCLVKDYFPEPVTVSWNSGALTS GVHTFPAVLQS SG
LY S LS SVVTVP S S SLGTQTYICNVNHKPSNTKVDKKVEPKS CDKTHTCPPCPAPEAEGAPS
VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST
YRVV S VLTVLHQ DWLNG KEYKCKV SNKALPAPIE KTI S KAKG Q PREP QVYTLPP S RD ELT
KNQVSLTCLVKGFYP SDIAVEWE SNGQPENNYK PPVLD SDGSFFLYSKLTVDKSRWQQ
GNVF S C S VMHE A LHNHYTQK S LS LS P GK
SEQ ID NO: 339 Fc17 (L234A, L235E, G237A)
ASTKGP SVFPLAP S S KS TS GGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SG
LY S LS SVVTVP S S S LGTQ TYI CNVNHKP SNTKVDK RVE P KS CDKTHTCPPCPAPEAEGAPSV
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F LF P P KP K D TLMI S RTP E VTCV VVD V S HE DP EVKFNWYVDGVE VHNAKTKPRE EQYNS
TY
RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTK
NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG
NVFSCSVMHEALHNHYTQKSLSLSPG
SEQ ID NO: 340 Fc18 (L234A, L235E, G237A)
ASTKGP SVFPLAP S S KS TS GGTAALGCLVKDYF PEPVTV SWNS GALTS GVHTF PAVLQ S SG
LYS LS SVVTVP SS SLGTQTYICNVNHKPSNTKVDK KVEPKS CDK THTCPP CP APE A EGA P S
VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST
YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMT
KNQVSLTCLVKGFYP SDI AVEWE SNGQPENNYK'TTPPVLDSD GSFFLYSKLTVDKSRWQQ
GNVFSCSVMHEALHNHYTQKSLSLSPG
SEQ ID NO: 341 Fc19 (L234A, L235E, G237A, P3315)
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG
LYS LS SVVTVP SS SLGTQTYICNVNHKPSNTKVDKKVEPKS CDKTHTCPPCPAPEAEGAPS
VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST
YRVVSVLTVLHQDWLNGKEYKCKVSNKALPA SIEK'TTSKAKGQPREPQVYTLPPSRDELT
KNQVSLTCLVKGFYPSDIAVEWESNGQPE'NNYK l'IPPVLDSDGSFFLYSKLTVDKSRWQQ
GNVFSCSVMHEALHNHYTQKSLSLSPG
SEQ ID NO: 342 Fc20 (L234A, L235E, G237A, P33 1S)
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG
LY S LS SVVTVP SS SLGTQTYICNVNHKPSNTKVDKRVEPKS CDKTHTCP P CP AP EAEGA PSV
FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
RVVSVLTVLHQDWLNGKEYKCKVSNKALPA SIEKTISKAKGQPREPQVYTLPPSREEMTK
NQVSLTCLVKGFYPSDIAVEWESNGQPENNYK 11 PPVLD SDG SFFLY SKLTVDKSRWQQG
NVF S C S VMHE A LHNHY TQ K S LS LS P G
SEQ ID NO: 343 Fc21 (L234A, L235E, G237A, P33 1S)
ASTKGPSVFPLAP S SKS TS GGTAALGCLVKDYFPEPVTV SWNS GA LTS GVHTF PAVLQ S SG
LYS LS SVVTVP SS SLGTQTYICNVNHKPSNTKVDKKVEPKS CDKTHTCPPCPAPEAEGAPS
VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST
YRVVSVLTVLHQDWLNGKEYKCKVSNKALPA SIEKTISKAKGQPREPQVYTLPPSREEMT
KNQVSLTCLVKGFYP SDIAVEWESNGQPENNYK IIPPVLDSDGSFFLYSKLTVDKSRWQQ
GNVFSCSVMHEALHNHYTQKSLSLSPG
SEQ ID NO: 344 Fc22 (L234A, L235A, P329A)
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG
LYS LS SVVTVP SS SLGTQTYICNVNHKPSNTKVDKKVEPKS CDKTHTCPPCPAPEAAGGP S
VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST
YRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVYTLPPSRDELT
KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK FIPPVLD S DGSFFLY SKLTVDKSRWQQ
GNVF S CSVM HE ALHNHYTQKS LSLS P GK
SEQ ID NO: 345 Fc23 (L234A, L235A, P329A)
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG
LYS LS SVV'TVP SS SLGTQTYICNVNHKPSN'TKVDK RVEPKS CDKTHTCPP CP AP EA AGGPS
VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST
YRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVYTLPPSREEMT
KN QV SLTCLVKGFYP SDIAVEWESNGQPENN YKTTPPVLDSDGSFFLY SKLTVDKSRWQQ
GNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO: 346 Fc24 (L234A, L235A, P329A)
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG
LYS LS SVVTVP SS SLGTQTYICNVNHKPSNTKVDKKVEPKS CDKTHTCPPCPAPEAAGGP S
VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST
YRVVS VLTVLHQDWLNGKEYKCKV SNK AL A APIEKTI S K A KGQPREPQVY'TLPP SREEMT
KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK l'IPPVLDSDGSFFLYSKLTVDKSRWQQ
GNVF SCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO: 347 Fc25 (D265A)
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ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG
LYS LS SVVTVP S S SLGTQTYICNVNHKPSNTKVDKKVEPKS CDKTHTCPPCPAPELLGGPSV
F LF P PKPK DTLMI S RTP E VTCVVV AV S HE DP EVKFNWYVDGVE VHNAKTKPRE EQYNS TY
RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK
NQVSLTCLVKGFYPSDIAVEWESNGQPENNYK l'IPPVLDSDGSFFLYSKLTVDKSRWQQG
NVF S C S VMHE A LHNHY TQ K S LS LS P GK
SEQ ID NO: 348 Fc26 (D265A)
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG
LYS LS SVVTVP S S SLGTQTYICNVNHKPSNTKVDKRVEPKS CDKTHTCPP CPAPELLGGP SV
FLFPPKPKD'TLMISR'TPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTK
NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKI.IPPVLDSDGSFFLYSKLTVDKSRWQQG
NVF S C S VMHE A LHNHY TQ K S LS LS P GK
SEQ ID NO: 349 Fc27 (D265A)
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG
LYSLS SVVTVPS S SLGTQTYICNVNHKP SNTKVDK KVEPKS CDK THTCPP CP APELLGGP SV
F LF P PKPK DTLMI S RTP VTCVVV AV S HE DP EVKFNWYVDGVE VHNAKTKPRE EQYNS TY
RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTK
NQVSLTCLVKGFYPSDIAVEWESNGQPENNYK l'IPPVLDSDGSFFLYSKLTVDKSRWQQG
NVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO: 350 Fc28 (N297G)
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG
LYS LS SVVTVP S S SLGTQTYICNVNHKPSNTKVDKKVEPKS CDKTHTCPPCPAPELLGGPSV
F LF P PKPK DTLMI S RTP E VTCVVVDV S HE DP EVK FNWYVDG VE VHNAKTKPRE EQY G S
TY
RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK
NQVSLTCLVKGFYPSD1AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG
NVF S C S VMHE A LHNHY TQ K S LS LS P GK
SEQ ID NO: 351 Fc29 (N297G)
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG
LY S LS SVVTVP S S SLGTQTYICNVNHKPSNTKVDKRVEPKS CDKTHTCP P CP AP ELLGGP S V
FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTY
RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTK
NQVSLTCLVKGFYPSDIAVEWESNGQPENNYK I IPPVLDSDGSFFLYSKLTVDKSRWQQG
NVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO: 352 Fc30 (N297G)
ASTKGPSVFPLAPS SKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS GVHTFPAVLQS SG
LYS LS SVVTVP S S SLGTQTYICNVNHKPSNTKVDKKVEPKS CDKTHTCPPCPAPELLGGPSV
FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTY
RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTK
NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKI.IPPVLDSDGSFFLYSKLTVDKSRWQQG
NVF S C S VMHE A LHNHY TQ K S LS LS P GK
SEQ ID NO: 353 Fc31 (D265A, N297A)
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG
LYS LS SVVTVP S S SLGTQTYICNVNHKPSNTKVDKKVEPKS CDKTHTCPPCPAPELLGGPSV
FLFPPKPKDTLM1SRTPE VTCV V VA V SHEDPEVKFN W Y VDGVE VHN AKTKPREEQY AS TY
RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK
NQVSLTCLVKGFYPSDIAVEWESNGQPENNYK FIPPVLDSDGSFFLYSKLTVDKSRWQQG
NVF S C S VM,HE A LHNHY TQ K S LS LS P GK
SEQ ID NO: 354 Fc32 (D265A, N297A)
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG
LY S LS SVVTVP S S SLGTQTYICNVNHKPSN'TKVDK RVEPKS CDK THTCP P CP A P ELLGGP S
V
F LF P PKPK DTLMI S RTP E VTCVVVAV S HE DP EVKFNWYVDGVE VHNAKTKPRE EQY A S TY
RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTK
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NQVSLTCLVKGFYPSDIAVEWE SNGQPENNYK I 'IPPVLD SDGSFFLYSKLTVDKSRWQQG
NVF S C S VMHE A LHNHY TQ K S LS LS P GK
SEQ ID NO: 355 Fc33 (D265A, N297A)
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG
LYS LS SVVTVP S S SLGTQTYICNVNHKPSNTKVDKKVEPKS CDKTHTCPPCPAPELLGGPSV
F LF P PKPK DTLMI S RTP E VTCVVV AV S HE DP EVKFNWYVDGVE VHNAKTKPRE EQY A S TY
RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTK
NQVSLTCLVKGFYPSDIAVEWE SNGQPENNYK l'IPPVLDSDGSFF LYSKLTVDKSRWQQG
NVF S C S VMHE A LHNHY TQ K S LS LS P GK
SEQ ID NO: 356 Fc34 (D265A, N297G)
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG
LYS LS SVVTVP S S SLGTQTYICNVNHKPSNTKVDKKVEPKS CDKTHTCPPCPAPELLGGPSV
F LF P PKPK DTLMI S RTP E VTCVVV AV S HE DP EVKFNWYVDGVE VHNAKTKPRE EQY GS TY
RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK
NQVSLTCLVKGFYPSDIAVEWE SNGQPENNYK1'IPPVLD SDGSFFLYSKLTVDKSRWQQG
NVF S CSVMHE A LHNHYTQK S LS LS P GK
SEQ ID NO: 357 Fc35 (D265A, N297G)
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSO
LYS LS SVVTVPS S SLGTQTYICNVNHKP SNTKVDKRVEPKS CDKTHTCPP CP AP ELLGGP SV
F LF P PKPK DTLMI S RTP E VTCVVV AV S HE DP EVKFNWYVDGVE VHNAKTKPRE EQY GS TY
RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTK
NQVSLTCLVKGFYPSDIAVEWE SNGQPENNYK I 'IPPVLD SDGSFFLYSKLTVDKSRWQQG
NVFS CS VMHEALHNHYTQKS LSLSPGK
SEQ ID NO: 358 Fc36 (D265A, N297G)
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG
LY S LS S V VTVP SS SLGTQTYICN VNHKPSNTKVDKKVEPKS CDKTHTCPPCPAPELLGGPSV
F LF P PKPK DTLMI S RTP E VTCVVV AV S HE DP EVKFNWYVDGVE VHNAKTKPRE EQY GS TY
RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTK
NQVSLTCLVKGFYPSDIAVEWE SNGQPENNYK 1 IPPVLD SDGSFFLYSKLTVDKSRWQQG
NVF S C S VMHE A LHNHY TQ K S LS LS P GK
SEQ ID NO: 359 Fc37 (L235A, G237A)
A S'TKGP SVFPLAP SSKSTSGGTA ALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQS SG
LYS LS SVVTVP S S SLGTQTYICNVNHKPSNTKVDKKVEPKS CDKTHTCPPCPAPELAGAPS
VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST
YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELT
KNQVSLTCLVKGFYP SDIAVEWE SNGQPENNYK IIPPVLDSDGSFFLYSKLTVDKSRWQQ
GNVF S C S VMHE ALHNHYTQK S LS LS P GK
SEQ ID NO: 360 Fc38 (L235A, G237A)
ASTKGP S VFPLAP S S KS TSGGTAALGCLVKDYFPEPVTV SW N SGALTSGVHTFPAVLQS SG
LY S LS SVVTVP S S SLG TQTYICNVNHKP SNTKVDKRVEPKS CDKTHTCP P CP AP ELA GAPSV
F LF P PKPK DTLMI S RTP E VTCVVVDV S HE DP EVKFNVVYVD GVE VHNAKTKPRE EQ YN S
TY
RVVSVUTVLHQDWLNGKEYKCKVSNK ALP AP IEK'TT S K A KGQPREPQVYTLPPSREEMTK
NQVSLTCLVKGFYPSDIAVEWE SNGQPENNYK I 'IPPVLD SDGSFFLYSKLTVDKSRWQQG
NVF S C S VMHE A LHNHY TQ K S LS LS P GK
SEQ ID NO: 361 Fc39 (L235A, 0237A)
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSO
LYS LS SVVTVP S S SLGTQTYICNVNHKPSNTKVDKKVEPKS CDKTHTCPPCPAPELAGAPS
VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST
YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA KG QPREP QVY TLPP SREE MT
KNQVSLTCLVKGFYP SDIAVEWE SNGQPENNYK IIPPVLDSDOSFFLYSKLTVDKSRWQQ
GNVF SCSVMHE A LHNHYTQ K S LS L S P GK
SEQ ID NO: 362 Fc40 (IgG4)
A S TKGP S VF P LAP C S RS TS E S TAALGCLVKDYF P E PV TV SWN S GALT S GVHTF P
AVLQ S SGL
YSLS SVVTVPS S SLGTKTYTCNVDHKP SNTKVDKRVE S KYGPP CP SCPAPEF LGGP SVFLFP
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PKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVS
VLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVS
LTCLVKGFYPSDIAVEWE SNGQPENNYK I IPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSC
SVMHEALHNHYTQKSLSLSLGK
SEQ ID NO: 363 (P329A)
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTEPAVLQSSG
LY S LS SVVTVP S S S LGTQ TYI CNVNHK P SNTKVDKK VE PK S CD K THTCP P CP A PE
LLGGP SV
F LF P PKPK DTLMI S RTP E VTCVVVDV S HE DP EVKFNVVYVD GVE VHNAKTKPRE EQ YN S
TY
RVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVYTLPPSRDELTK
NQVS LTCLVKGFYP S DI AVEWE SNGQPE'NNYK'TTP PVLDSDGSFFLYSKLTVDKSRWQQG
NVFS CSVM HEALHNHYTQKSLS LS PG K
SEQ ID NO: 364 (L234E, L235F, P331 S)
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG
LY S LS SVVTVP SS S LGTQ TYI CNVNHKP SNTKVDKKVE PK S CD KTHTCPP CPAPE EFGGPSV
F LF P PKPK DTLMI S RTP E VTCVVVDV S HE DP EVKFNVVYVD GVE VHNAKTKPRE EQYNS TY
RVVSVLTVLHQDWLNGKEYKCKVSNKALPA SIEK'TTSKAKGQPREPQVYTLPPSRDELTK
NQVSLTCLVKGFYPSDIAVEWE SNGQPE'NNYK 1IPPVLD SDGSFFLYSKLTVDKSRWQQG
NVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO: 365 (5228P)
A S TKGP S VF P LAP C S RS TS E S TAALGCLVKDYF P E PV TV SWN S GALT S GVHTF P
AVLQ S SGL
YSLS SVVTVP S SSLGTKTYTCNVDHKP SNTKVDKRVE SKYGPPCPPCPAPEFLGGP SVFLFP
PKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVS
VLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVS
LTCLVKGFYPSDIAVEWE SNGQPENNYK 1 '1PPVLDSDG SFFLY SRLTVDKSRWQEGNVFSC
SVMHEALHNHYTQKSLSLSLGK
SEQ ID NO: 366 (5228P, L235E)
A S TKGP S VF P LAP C S RS TS E S TAALGCLVKDYF P E PV TV SWN S GALT S GVHTF P
AVLQ S SGL
YSLS SVVTVPS SSLGTKTYTCNVDHKP SNTKVDKRVE S KYGPP CP PCPAPEFEGGP SVFLFP
PKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVS
VLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVS
LTCLVKGFYPSDIAVEWE SNGQPENNYK I 'IPPVLDSDGSFFLY SRLTVDKSRWQEGNVFSC
SVMHEALHNHYTQKSLSLSLGK
SEQ ID NO: 367 (5228P, F234A, L235A)
ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL
YSLS SVVTVPS SSLGTKTYTCNVDHKP SNTKVDKRVE SKYGPP CP PCPAPEAAGGPSVFLF
PPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVV
SVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVS
LTCLVKGFYPSDIAVEWESNGQPENNYK 11PPVLDSDGSFFLYSRLTVDKSRWQEGNVFSC
SVMHEALHNHYTQKSLSLSLGK
SEQ ID NO: 368 (L234A, L235A)
QV Q LVQ S GAE VKKP GA S V KV S CKA S GF DIQ DTYMIHWVK Q RP GQ GLEWMGRIDPA S
GHT
KYDPKFQVRVTITRDTSTSTVYLELS SLRSEDTAVYYCARSGGLPDVWGQGTTVTVS SA ST
KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS
LS SVVTVPS S SLGTQTYICNVNHKP SNTKVDKKVEPKS CDKTHTCPPCPAPE AA GGP SVFLF
PPKPKDTLMI S RTPE VTCV V VDV SHE DPE VKFN WY VDGVEVHNAKTKPREEQYN STYRV
VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQ
V S LTCLVKGFYP S D IAVEWE SNGQ PENNYKTTPPVLD S DGSFF LY S KLTVD KS RWQQGNV
FSCSVM,HEALHNHYTQKSLSLSPGK
SEQ ID NO: 369 (L235E)
QV Q LVQ S GA E VKKP GA S VKV S CKA S GF D IQ D TY MHWVKQ RP GQ GLEW MGRIDPA
SGHT
KYDPKFQVRVTITRDTSTSTVYLELS SLRSEDTAVYYCARSGGLPDVWGQGTTVTVS SA ST
KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS
LS SVVTVPS S SLGTQTYICNVNHKP SNTKVDKKVEPKS CDKTHTCPPCPAPE LEGGPSVFLF
PPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV
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VS VLTVLHQDWLNGKEYKCKV SNKALPAPIEKTI S KAKGQPREP QVYTLPP S RDELTKNQ
V S LTCLVKGFYP SDIAVEWE SNGQ P ENNYKTTP PVLD S DGSF F LY S KLTVD K S RWQ Q GNV
F S CS VM HEALHNHYTQKSLSLSPGK
SEQ ID NO: 370 (L234A, L235A, G237A)
QVQLVQSGAEVKKPGASVKVSCKASGEDIQDTYMEWVKQRPGQGLEWMGRIDPASGHT
KYDPKFQVRVTITRDTSTSTVYLELSSLRSEDTAVYYCARSGGLPDVWGQGTTVTVSSAST
KGPSVFPLAPS SK STS GGTA ALGCLVKDYFPEPVTVSWN SGA LTS GVHTFP A VLQ S SGLYS
LS SVVTVPS S SLGTQTYICNVNHKP SNTKVDKKVEPKS CDKTHTCPPCPAPE AA GAP SVFLF
P P KP KD TLMI S RTP E VTCVVVDV S HE D P E VKFNWYVDGVEVHNAKTKP REE QYNSTYRV
VSVLTVLHQ DWLNGK EYK CKVSNK A LP A PIEK'TT S K AKGQP REP QVYTLPP SRDELTKNQ
V S LTCLVKG FYP SDIAVEWE SNG Q P ENNYK 1'1P PVLD S DG SF F LY S KLTVD K S RWQ
Q GNV
F S CS VM HEALHNHYTQKSLSLSPGK
SEQ ID NO: 371 (L234A, L235E, G237A)
QV Q LVQ S GA E VKKP GA S VKV S CKA S GF IQ D TY MHWVKQ RP GQ GLEWMGRIDP A S
GHT
KYDPKFQVRVTITRDTSTSTVYLELSSLRSEDTAVYYCARSGGLPDVWGQGTTVTVSSAST
KGPSVFPLAPS SK STS GGTA ALGCLVKDYFPEPVTVSWN SGA LTS GVHTFP A VLQ S SGLYS
LS SVVTVPS S SLGTQTYICNVNHKP SNTKVDKKVEPKS CDKTHTCPPCPAPE AEGAPSVFLF
P P KP KD TLMI S RTP E VTCVVVDV S HE D P E VKFNWYVDGVEVHNAKTKP REE QYN STYRV
VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP S RDELTKNQ
V S LTCLVKGFYP SDIAVEWE SNGQ P EN NYK 1'1P PVLD S DGSF F LY S KLTVD K S RWQ Q
GNV
F S CS VM HEALHNHYTQKSLSLSPGK
SEQ ID NO: 372 (L234A, L235A, P329A)
QV Q LVQ S GA E VKKP GA S VKV S CKA S GF IQ D TY MHWVKQ RP GQ GLEWMGRIDP A S
GHT
KYDPKFQVRVTITRDTSTSTVYLELSSLRSEDTAVYYCARSGGLPDVWGQGTTVTVSSAST
KGPSVFPLAPS SKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS
LS SVVTVPS S SLGTQTYICN VNHKP SN TKVDKKVEPKS CDKTHTCPPCPAPE AAGGP SVFLF
P P KP KD TLMI S RTP E VTCVVVDV S HE D P E VKFNWYVDGVEVHNAKTKP REE QYN STYRV
VSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQ
VSLTCLVKGFYP SDIAVEWE SNGQPENNYK IIPPVLD SDGSFFLYSKLTVDKSRWQQGNV
F S CS VM HEALHNHYTQKSLSLSPGK
SEQ ID NO: 373 (L234A, L235A, P329G)
QV Q LVQ S GA E VKKP GA S VKV S CKA S GF IQ D TY MHWVKQ RP GQ GLEWMGRIDP A S
GHT
KYDPKFQVRVTITRDTSTSTVYLELSSLRSEDTAVYYCARSGGLPDVWGQGTTVTVSSAST
KGPSVFPLAPS SKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS
LS SVVTVPS S SLGTQTYICNVNHKP SNTKVDKKVEPKS CDKTHTCPPCPAPEAAGGP SVFLF
P P KP KD TLMI S RTP E VTCVVVDV S HE D P E VKFNWYVDGVEVHNAKTKP REE QYN STYRV
VSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQ
V S LTCLVKGFY P S DIA VEWE SN GQPENNYKTTPPVLD SDGSF FLY SKLTVDKSRWQQGN V
F S CS VM HEALHNHYTQKSLSLSPGK
SEQ ID NO: 374 (P329A)
QV Q LVQ S GA E VKKP GA S VKV S CKA S GF IQ D TY MHWVKQ RP GQ GLEWMGRIDP A S
GHT
KYDPKFQVRVTITRDTSTSTVYLELS SLRSEDTAVYYCARSGGLPDVWGQGTTVTVS SA ST
KGPSVFPLAPS SKSTS GGTAALGCLVKDY FPEPVTV SWNSGALTS GVHTFPAVLQ S SGLYS
LS SVVTVPS S SLGTQTYICNVNHKP SNTKVDKKVEPKS CDKTHTCPPCPAPELLGGPSVFLF
P P KP KD TLMI S RTP E VTCVVVDV S HE D P E VKFNWYVDGVEVHNAKTKP REE QYN STYRV
VSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQ
V S LTCLVKGFYP S IAVEWE SNGQPENNYKTIPPVLDSDGSFF LYSKLTVDKSRWQQGNV
FSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO: 375 (L234E, L235F, P33 1S)
QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVKQRPGQGLEWMGRIDPASGHT
KYDPKFQVRVTITRDTSTSTVYLELS SLRSEDTAVYYCARSGGLPDVWGQGTTVTVS SA ST
KGPSVFPLAPS SKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYS
LS SVVTVPS S SLGTQTYICNVNHKP SNTKVDKKVEPKS CDKTHTCPPCPAPEEFGGPSVFLF
P P KP KD TLMI S RTP E VTCVVVDV S HE D P E VKFNWYVDGVEVHNAKTKP REE QYN STYRV
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VSVLTVLHQ DWLNGKEYKCKVSNKA LPASIEKTI S KAKGQP REP QVYTLPP S RDELTKNQ
V S LTCLVKGFYP SDIAVEWE SNGQ P ENNYKTTP PVLD S DGSF F LY S KLTVD K S RWQ Q GNV
FSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO: 376 (D265A, N297G)
QV Q LVQ S GA E VKKP GA S VKV S CKA S GF D IQ D TY MHWVKQ RP GQ GLEWMGRIDP A S
GHT
KYDPKF QVRVTI TRDTS TS TVYLELS SLRSEDTAVYY CARS GGLPDVWGQ GITVTV S SAS T
KGPSVFPLAPS SK STSGGTA ALGCLVKDYFPEPVTVSWN SGA LTS GVHTFP A VLQ S SGLYS
LS SVVTVPS S SLGTQTYICNVNHKP SNTKVDKKVEPKS CDKTHTCPPCPAPE LLGGP SVFLF
PPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY GS TYRV
VSVLTVLHQ DWLNGK EYK CKVSNK A LP APIE K'TT SK AKGQPREPQVY'TLPPSRDELTKNQ
VSLTCLVKGFYP SDIAVEWE SNG QPENNYK1'IPPVLDSDG SF FLYS KLTVDKS RWQ QGNV
FSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO: 377 (N297G)
QV QLVQ S GAE VKKP GA S VKV S CKASGFDIQDTYMHWVKQRP GQGLEWMGRIDPA SGHT
KYDPKFQVRVTITRDTSTSTVYLELSSLRSEDTAVYYCARSGGLPDVWGQGTIVTVSSAST
KGPSVFPLAPS SK STSGGTA ALGCLVKDYFPEPVTVSWN SGA LTS GVHTFP A VLQ S SGLYS
LS SVVTVPS S SLGTQTYICNVNHKP SNTKVDKKVEPKS CDKTHTCPPCPAPE LLGGP SVFLF
PPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY GS TYRV
VSVLTVLHQ DWLNGKEYKCKVSNKA LP APIE KIT SKAKGQPREP QVYTLPP S RDELTKNQ
V S LTCLVKGFYP SDIAVEWE SNGQ P ENNYK 1'1P PVLD S DGSF F LY S KLTVD K S RWQ Q
GNV
FSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO: 378 (S228P)
QV QLVQ S GAE VKKP GA S VKV S CKASGFDIQDTYMHWVKQRP GQGLEWMGRIDPA SGHT
KYDPKFQVRVTITRDTSTSTVYLELSSLRSEDTAVYYCARSGGLPDVWGQGTIVTVSSAST
KGP S VF P LA P C S RS TS E S TAALGCLVKDYF P E PVTV S WN S GA LTS GVHTF PAVLQ
S SGLYSL
S S V VTVP S S SLGTKTYTCN VDHKPSNTKVDKRVE SKY GPPCP PCPAPEFLGGPSVFLFPPKP
KDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVL
TVLHQDWLNGKEYKCKVSNKGLP S SIEKTISKAKGQ PREP QVY TLPP SQEEMTKN QVS Lir
LVKGFYPSDIAVEWE SNGQPENNYKTTPPVLD SDGSFFLYS RLTVDKSRWQEGNVF SCS V
MHEALHNHYTQKSLSLSLGK
SEQ ID NO: 379 (5228P, L235E)
QV Q LVQ S GA E VKKP GA S VKV S CKA S GF D IQ D TY MHWVKQ RP GQ GLEWMGRIDP A S
GHT
KYDPKFQVRVTITRDTSTSTVYLELS SLRSEDTAVYYCARSGGLPDVWG QGTTVTVS S AS T
KGP S VF P LA P C S RS TS E S TAALGCLVKDYF P E PVTV S WN S GA LTS GVHTF PAVLQ
S SGLYSL
S SVVTVP SS SLGTKTYTCNVDHKPSNTKVDKRVE S KY GP P CP PCPAPEFEGGPSVFLFPPKP
KDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVL
TVLHQDWLNGKEYKCKVSNKGLP S SIEKTI S KAKGQPREP QVYTLPP SQEEMTKNQV S Lir
LVKGFY P S DIAV EWE SNGQPENN YKTTPPVLD SDGSFFLY SRLTVDKSRWQEGN V F SCS V
MHEALHNHYTQKSLSLSLGK
SEQ ID NO: 380 (5228P, F234A, L235A)
QV Q LVQ S GA E VKKP GA S VKV S CKA S GF D IQ D TY MHWVKQ RP GQ GLEWMGRIDP A S
GHT
KYDPKFQVRVTITRDTSTSTVYLELS SLRSEDTAVYYCARSGGLPDVWGQGTTVTVS S A ST
KGP S VF P LA P C S RS TS E S TAALGCLVKDY F P E PV TV SWN S GALTS GVHTF P AVL
Q S SGLYSL
S SVVTVP S S SLGTKTYTCNVDHKPSNTKVDKRVE S KY GP P CP PCPAPEAAGGPSVFLFPPKP
KDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVL
TVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTC
LVKGFYPSDIAVEWE SNGQPENNYKTTPPVLD SDGSFFLYS RLTVDKSRWQEGNVF SCSV
MHEALHNHYTQKSLSLSLGK
SEQ ID NO: 381
EIVLTQ SP GTLSLSP GE RATLS CRAS S SVSYMYWYQQKPGQAPRPLIYATSNLASGIPDRF S
GSGSG'TDF'TUTT SRLEPEDF A VYYCQQWEGNPRTFGGG'TKLE1KR'TVA A P S VF1FPP SDEQL
KSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKAD
YEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO: 382 (Light chain of control antibody that binds only to TL1A
trimer)
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EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRAT
GIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPWTFGQGTKVEIKRTVAAP
SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDS
KD STY SL SSTLTL SKADYEKHKVYACEVTHQGL SSPVTK SFNRGEC
SEQ ID NO: 383 (Heavy chain of control antibody that binds only to TL1A
trimer)
QVQLVQ SGAEVKKPGASVKVSCKASGYDFTYYGISWVRQAPGQGLEWMGWIST
YNGNTHYARMLQGRVTMTTDTSTRTAYMELRSLRSDD TAVYYCARENYYGSGA
YRGGMDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV
TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK
VDKKVEPK SCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDV
SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY
KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS
DIAVEWESNGQPENNYKTTPPVLD SD G SFFLY SKLTVDK SRWQQGNVF SC SVM_HE
ALHNHYTQKSLSLSPG
1005991 The foregoing description of various embodiments known to the
applicant at this
time of filing the application has been presented and is intended for the
purposes of
illustration and description. The present description is not intended to be
exhaustive nor
limited to the precise form disclosed and many modifications and variations
are possible in
the light of the above teachings. The embodiments described serve to explain
principles and
practical applications, and to enable others skilled in the art to utilize the
various
embodiments, optionally with various modifications, as are suited to the
particular use
contemplated. Therefore, it is intended that the disclosure not be limited to
the particular
embodiments disclosed.
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